A Review of Red Yeast Rice, a Traditional Fermented Food in Japan and East Asia: Its Characteristic Ingredients and Application in the Maintenance and Improvement of Health in Lipid Metabolism and the Circulatory System

Abstract

Red yeast rice has been used to produce alcoholic beverages and various fermented foods in China and Korea since ancient times; it has also been used to produce tofuyo (Okinawan-style fermented tofu) in Japan since the 18th century. Recently, monacolin K (lovastatin) which has cholesterol-lowering effects, was found in some strains of Monascus fungi. Since statins have been used world-wide as a cholesterol-lowering agent, processed foods containing natural statins are drawing attention as materials for primary prevention of life-style related diseases. In recent years, large-scale commercial production of red yeast rice using traditional solid-state fermentation has become possible, and various useful materials, including a variety of monascus pigments (polyketides) that spread as natural pigments, in addition to statins, are produced in the fermentation process. Red yeast rice has a lot of potential as a medicinal food. In this paper, we describe the history of red yeast rice as food, especially in Japan and East Asia, its production methods, use, and the ingredients with pharmacological activity. We then review evidence of the beneficial effects of red yeast rice in improving lipid metabolism and the circulatory system and its safety as a functional food.

Full text

molecules
Review
A Review of Red Yeast Rice, a Traditional Fermented Food in
Japan and East Asia: Its Characteristic Ingredients and
Application in the Maintenance and Improvement of Health in
Lipid Metabolism and the Circulatory System
Hiroyuki Fukami 1, *, Yuki Higa 1, Tomohiro Hisano 1, Koichi Asano 1, Tetsuya Hirata 1and Sansei Nishibe 2


Citation: Fukami, H.; Higa, Y.;
Hisano, T.; Asano, K.; Hirata, T.;
Nishibe, S. A Review of Red Yeast
Rice, a Traditional Fermented Food in
Japan and East Asia: Its Characteristic
Ingredients and Application in the
Maintenance and Improvement of
Health in Lipid Metabolism and the
Circulatory System. Molecules 2021,
26, 1619. https://doi.org/10.3390/
molecules26061619
Academic Editors: Alessia Fazio and
Pierluigi Plastina
Received: 28 December 2020
Accepted: 5 February 2021
Published: 15 March 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Central R&D Laboratory, KOBYASHI Pharmaceutical Co., Ltd., Ibaraki 567-0057, Japan;
y.higa@kobayashi.co.jp (Y.H.); t.hisano@kobayashi.co.jp (T.H.); ko.asano@kobayashi.co.jp (K.A.);
t.hirata@kobayashi.co.jp (T.H.)
2Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari 061-0293, Japan;
nishibe@hoku-iryo-u.ac.jp
*Correspondence: h.fukami@kobayashi.co.jp; Tel.: +81-80-3452-9483; Fax: +81-72-640-0137
Abstract:
Red yeast rice has been used to produce alcoholic beverages and various fermented
foods in China and Korea since ancient times; it has also been used to produce tofuyo (Okinawan-
style fermented tofu) in Japan since the 18th century. Recently, monacolin K (lovastatin) which
has cholesterol-lowering effects, was found in some strains of Monascus fungi. Since statins have
been used world-wide as a cholesterol-lowering agent, processed foods containing natural statins
are drawing attention as materials for primary prevention of life-style related diseases. In recent
years, large-scale commercial production of red yeast rice using traditional solid-state fermentation
has become possible, and various useful materials, including a variety of monascus pigments
(polyketides) that spread as natural pigments, in addition to statins, are produced in the fermentation
process. Red yeast rice has a lot of potential as a medicinal food. In this paper, we describe the history
of red yeast rice as food, especially in Japan and East Asia, its production methods, use, and the
ingredients with pharmacological activity. We then review evidence of the beneficial effects of red
yeast rice in improving lipid metabolism and the circulatory system and its safety as a functional food.
Keywords:
red yeast rice; Monascus fungi; solid-state fermentation; monacolin; statin; LDL-cholesterol;
polyketide; pigment; lipid metabolism; cardiovascular system
1. Introduction: Overview of Red Yeast Rice, Its History, Production Method, and Use
1.1. The History behind Koji (Yeast Grain) and Red Yeast Rice (Red Koji)
Every country in the world has its own traditional food culture, and quite a few
countries have their own brewed foods, made using different fermentation mechanisms.
In contrast to western countries, where malt and fruit juice are used for fermentation, in
Eastern and Southeastern Asia, fermented foods are produced using rice and beans malted
with filamentous fungus such as Aspergilli. Fungi are widely used since the areas have a
climate of high temperatures and humidities.
Koji is made by breeding molds that can be used for food fermentation on grains such
as rice, wheat, and soybeans. Miso, soy-sauce, vinegar, mirin (sweet sake), pickles, sake
(Japanese rice wine), and distilled spirit are all made from various Koji grains which play a
central role in “Wasyoku”, a food culture in Japan.
There are various types of koji and koji molds (also called koji fungi): yellow koji (made
with A. oryzae), used to produce miso, soy-sauce, mirin and sake; black koji (made with A.
awamori), used to produce awamori (Okinawan distilled spirit); and black koji or white koji
(made with A. Kawachii), used to produce syochuu (Japanese distilled spirits). Red yeast rice
(red yeast grain, red koji,Beni-Koji), made with Monascus fungi, has been used to produce
Molecules 2021,26, 1619. https://doi.org/10.3390/molecules26061619 https://www.mdpi.com/journal/molecules

Molecules 2021,26, 1619 2 of 20
Tofunyu (fermented bean curd) in Taiwan and China since ancient times and has also been
used to produce tofuyo (Okinawan style fermented bean curd) in Japan.
Monascus fungi produce red pigments and the koji produced with Monascus fungi
exhibit a deep red color (Figure 1). These red pigments have been used industrially since
the 1950s in Japan. For example, they have been used in processed fish paste products,
such as crab-flavored-fish cakes and processed meat products, such as ham and sausages.
Recently, they have been widely used in various foods including bread, confectionaries
and beverages, such as amazake (fermented rice drink).
Molecules 2021, 26, x FOR PEER REVIEW 2 of 20
(made with A. Kawachii), used to produce syochuu (Japanese distilled spirits). Red yeast
rice (red yeast grain, red koji, Beni-Koji), made with Monascus fungi, has been used to pro-
duce Tofunyu (fermented bean curd) in Taiwan and China since ancient times and has also
been used to produce tofuyo (Okinawan style fermented bean curd) in Japan.
Monascus fungi produce red pigments and the koji produced with Monascus fungi
exhibit a deep red color (Figure 1). These red pigments have been used industrially since
the 1950s in Japan. For example, they have been used in processed fish paste products,
such as crab-flavored-fish cakes and processed meat products, such as ham and sausages.
Recently, they have been widely used in various foods including bread, confectionaries
and beverages, such as amazake (fermented rice drink).
Figure 1. Appearance of red yeast rice.
Red yeast rice is recorded in Bencao Gangmu (Compendium of Materia Medica), a
representative book on Chinese medicine, written in 1596 which has been highly valued
since ancient times in China. Lovastatin (monacolin K), which has cholesterol lowering
effects, was found as an active ingredient from Monascus fungi [1–3]. Statins such as lovas-
tatin and its analogs are used world-wide as serum cholesterol lowering agents which are
used as first-line drugs for atherosclerotic diseases. Evidence for the beneficial and plei-
otropic effects of statins has been reported, and further accumulation of evidence is ex-
pected in the future. Red yeast rice also contains lovastatin, and although it is currently
used as a functional food, it could be used in the prevention of life-style related diseases
to reduce metabolic syndrome and the metabolic domino, through the improvement of
dietary habits.
In this study, we review Monascus fungi: their history, production methods of red
yeast rice, foods made using red yeast rice, characteristic ingredients, evidence of potential
beneficial effects to improve lipid metabolism and the circulatory system, and safety.
1.2. Monascus Fungi and Red Yeast Rice
Monascus fungi are taxonomically classified into Hemiascomycetes; they are filamen-
tous fungi belonging to the Ascomycetes class, similar to Aspergillus, which are used in the
production of miso, soy-sauce and sake. These Monascus fungi are called red koji mold (or
red koji fungi) because they produce red pigments; approximately 20 strains have been
identified so far (Table 1). Most of the Monascus fungi were found in red yeast rice and
brewed foods or beverages produced with red yeast rice in China, Taiwan, or Korea from
the second half of the 1920s to the first half of the 1930s [4]. About 50 strains of Monascus
fungi are preserved in the Biological Resource Center, Department of Biotechnology, Na-
tional Institute of Technology and Evaluation (NITE) in Japan (Table 2) [5].
Figure 1. Appearance of red yeast rice.
Red yeast rice is recorded in Bencao Gangmu (Compendium of Materia Medica), a
representative book on Chinese medicine, written in 1596 which has been highly valued
since ancient times in China. Lovastatin (monacolin K), which has cholesterol lowering
effects, was found as an active ingredient from Monascus fungi [
1
–
3
]. Statins such as
lovastatin and its analogs are used world-wide as serum cholesterol lowering agents which
are used as first-line drugs for atherosclerotic diseases. Evidence for the beneficial and
pleiotropic effects of statins has been reported, and further accumulation of evidence is
expected in the future. Red yeast rice also contains lovastatin, and although it is currently
used as a functional food, it could be used in the prevention of life-style related diseases
to reduce metabolic syndrome and the metabolic domino, through the improvement of
dietary habits.
In this study, we review Monascus fungi: their history, production methods of red
yeast rice, foods made using red yeast rice, characteristic ingredients, evidence of potential
beneficial effects to improve lipid metabolism and the circulatory system, and safety.
1.2. Monascus Fungi and Red Yeast Rice
Monascus fungi are taxonomically classified into Hemiascomycetes; they are filamentous
fungi belonging to the Ascomycetes class, similar to Aspergillus, which are used in the
production of miso, soy-sauce and sake. These Monascus fungi are called red koji mold (or
red koji fungi) because they produce red pigments; approximately 20 strains have been
identified so far (Table 1). Most of the Monascus fungi were found in red yeast rice and
brewed foods or beverages produced with red yeast rice in China, Taiwan, or Korea from the
second half of the 1920s to the first half of the 1930s [
4
]. About 50 strains of Monascus fungi
are preserved in the Biological Resource Center, Department of Biotechnology, National
Institute of Technology and Evaluation (NITE) in Japan (Table 2) [5].

Molecules 2021,26, 1619 3 of 20
Table 1. Typical Monascus fungi and their isolation source.
Strain Source
M. purpureus Red yeast rice, malted rice (miquzi in Chinese) (China, Korea, Taiwan)
M. anka Red yeast rice (Taiwan), malted rice of red nyufu
M. anka var. rubellus Lees from the making process of red Laojiu (Chinese alcoholic beverage)
M. barkeri Malted rice for samutu-syu (Chinese red alcoholic beverage)
M. albidus Chantofu (Shanghai)
M. araneosus Malted rice for gaoliangilu (Chinese distilled spirit, Northeastern China)
M. furiginosus Malted rice (Guizhou Province, China)
M. major Malted rice (Fuzhou, China)
M. albidus var. glaber Malted rice (Fuzhou, China)
M. pilosus Malted rice for gaoliangilu (Fengtian, China)
M. rubropanctatus Powdered malted rice for medicinal wine (Incheon, Korea)
M. pubigerus Malted rice for gaoliangilu (Liaoyang, China)
M. rubinosus Malted rice (Guangdong Province)
M. serorubescens Red funyu (Hong Kong)
M. vitreus Red funyu (Hong Kong)
M. kaoliang Malted rice for gaoliangilu (Taiwan)
M. ruber Silage, soil, rotten fruit etc.
M. paxi Dead branch and leaves of plants
Table 2.
Representative Monascus fungi preserved at the Biological Resource Center (NBRC), NITE
in Japan.
Strain
M. anka Nakazawa et Sato NBRC 4478
M. purpreus Went NBRC 4513
M. anka Nakazawa et Sato (T. Hasegawa) NBRC 6540
M. major Sato NBRC 4485
M. ruber van Tieghem NBRC 4492
M. pubigerus Sato NBRC 4521
M. araneosus Sato NBRC 4482
M. rubiginosus Sato NBRC 4484
M. anka var. rubellus Sato NBRC 5965
M. ruber van Tieghem (S. Udagawa) NBRC 9203
M. pilosus Sato (FAT) NBRC 4520
M. fuliginosus Sato NBRC 4483
M. pilosus Sato NBRC 4480
M. paxii Lingelsheim NBRC 8201
M. vitreus Sato NBRC 4532
M. vitreus Sato (J. Nicot) NBRC 7537
M. albidus Sato NBRC 4489
M. anka var. rubellus Sato (H. Iizuka) NBRC 6085
M. serorubescens Sato NBRC 4487
M. albidus var. glaber Sato NBRC 4486
M. serorubescens Sato (FAT) NBRC 4525
1.3. Production of Red Yeast Rice
Red yeast rice is documented as Chinese herbal cuisine that improves blood circulation
in Nichiyo-Honzo, a Chinese herbology book written by Duan Wu in 1329. Red yeast rice
was also called tan-giku, and its production method is described in Tiangong Kaiwu, a
compendium on industry, agriculture and artisanry, written by Song Ying in the 17th
century in China (Figure 2) [
4
,
6
]. In brief, after soaking in water for 7 days, polished rice is
steamed, and the lees of Shaoxing wine are added as seed fungi and cultured in a tile room
for about 1 week. Interestingly, the method is very similar to that used in the production of
yellow koji in Japan. Monascus fungi (red koji fungi) have low proliferative ability, and about
1 week is required for the production of red yeast rice, though only 2 days are required for

Molecules 2021,26, 1619 4 of 20
that of yellow koji. The long-term culture increases the chance of contamination by various
germs; therefore, the area of each production process is kept thoroughly clean, and the
aseptically cultured red yeast rice is used as the seed fungus.
Molecules 2021, 26, x FOR PEER REVIEW 4 of 20
compendium on industry, agriculture and artisanry, written by Song Ying in the 17th cen-
tury in China (Figure 2) [4,6]. In brief, after soaking in water for 7 days, polished rice is
steamed, and the lees of Shaoxing wine are added as seed fungi and cultured in a tile room
for about 1 week. Interestingly, the method is very similar to that used in the production
of yellow koji in Japan. Monascus fungi (red koji fungi) have low proliferative ability, and
about 1 week is required for the production of red yeast rice, though only 2 days are re-
quired for that of yellow koji. The long-term culture increases the chance of contamination
by various germs; therefore, the area of each production process is kept thoroughly clean,
and the aseptically cultured red yeast rice is used as the seed fungus.
Figure 2. Production method of red yeast rice described in “Tiangong Kaiwu”. Rice inoculated with Monascus fungi is di-
vided between several bamboo trays, which are placed on shelves to maintain good air circulation. Ambient air during
the culture is a key factor. The room in which the shelves are placed must be wide and there must be a high ceiling. The
room must also be facing south to avoid afternoon sunlight and its temperature should be controlled. Rice inoculated with
the fungi should be mixed up and down 3 times every 2 hours.
Red yeast rice itself has been used in the coloring of foods, meat in particular, in
China and Taiwan since ancient times. Red pigments extracted and isolated from red yeast
rice have been produced as natural pigments on an industrial scale since 1945. Since the
carcinogenicity of synthetic red pigments was discovered, the consumption of natural pig-
ments (red yeast rice pigment) made by Monascus fungi has increased.
The traditional method for the production of red yeast rice-related foods was the
solid-state culture method described above; however, the pigments are now industrially
produced by simple processes of extraction and concentration from red yeast rice, prolif-
erated by an aerated and agitated culture method (liquid-state culture) (Figure 3) [7].
Figure 2.
Production method of red yeast rice described in “Tiangong Kaiwu”. Rice inoculated with Monascus fungi is
divided between several bamboo trays, which are placed on shelves to maintain good air circulation. Ambient air during
the culture is a key factor. The room in which the shelves are placed must be wide and there must be a high ceiling. The
room must also be facing south to avoid afternoon sunlight and its temperature should be controlled. Rice inoculated with
the fungi should be mixed up and down 3 times every 2 h.
Red yeast rice itself has been used in the coloring of foods, meat in particular, in
China and Taiwan since ancient times. Red pigments extracted and isolated from red yeast
rice have been produced as natural pigments on an industrial scale since 1945. Since the
carcinogenicity of synthetic red pigments was discovered, the consumption of natural
pigments (red yeast rice pigment) made by Monascus fungi has increased.
The traditional method for the production of red yeast rice-related foods was the
solid-state culture method described above; however, the pigments are now industri-
ally produced by simple processes of extraction and concentration from red yeast rice,
proliferated by an aerated and agitated culture method (liquid-state culture) (Figure 3) [
7
].
Molecules 2021, 26, x FOR PEER REVIEW 5 of 20
Figure 3. Solid-state/liquid-state culture method of red yeast rice.
1.4. Brewed Foods Produced Using Red Yeast Rice
Red yeast rice has been widely used as a material for the production of anchu (Chi-
nese red wine), tofunyu (fermented bean curd), and a coloring agent for foods or a preserva-
tive for meat in China and Taiwan.
The production technique for red Laojiu (Chinese alcohol beverage) originated in a
Fijian Province in China and was introduced into Taiwan about 200 years ago. It is said to
be the origin of the present-day Taiwanese red alcoholic beverage called Hon-ru-chu that
is popular at festivals and wedding ceremonies [4].
Tofunyu, also called funyu or nyuhu, is a flavored food produced using mold prolifer-
ated on bean cakes which are salted and then matured by soaking in unrefined sake [8,9].
Fermented bean curd produced using red yeast rice is often called red funyu, and it is said
to have originated the period about 1500 years ago in China. Red funyu is now produced
in Jiangsu, Zhejiang, Sichuan, Hong Kong and Taiwan.
Brewed foods in East Asia were introduced to Japan sometime long ago. Tofuyo, a
type of fermented bean curd (Figure 4), is a fermented food from Okinawa which is similar
to red funyu in China and Taiwan. Tofuyo was introduced to Japan as “a fragrant and
sweet/tasty food that improved digestive function and was effective in the treatment of
various diseases” according to Gyozen Honzo (Edible plants of Okinawa), a book on dietary
plants compiled in 1832 [4]. It was highly valued as a nutritional food and side dish in the
1800s. At present, tofuyo is produced by a novel method using aged sake, awamori (Okina-
wan distilled spirit).
Figure 4. Tofuyo, a food that has been passed down the generations in Okinawa, Japan.
Funyu has been eaten for more than 1000 years in China. In Japan, it is prepared using
miso produced with red yeast rice. In 1985, a Monuscus fungi was used to brew miso pre-
pared by a traditional method, and it has been in use ever since [10].
Traditional solid-state fermentation method since ancient
Polished rice
Water
Inoculation of Monascus fungi
Sterilization Culture Drying Grinding Product
Liquid-state fermentation method
Culture components
Wat e r
Red yeast rice solution
Product
Jar fermenter Sterilization Culture Sparation
Filtration Concentration Flush heat pasteurization Freeze drying
Inoculation of Monascus fungi
Figure 3. Solid-state/liquid-state culture method of red yeast rice.

Molecules 2021,26, 1619 5 of 20
1.4. Brewed Foods Produced Using Red Yeast Rice
Red yeast rice has been widely used as a material for the production of anchu (Chinese
red wine), tofunyu (fermented bean curd), and a coloring agent for foods or a preservative for
meat in China and Taiwan.
The production technique for red Laojiu (Chinese alcohol beverage) originated in a
Fijian Province in China and was introduced into Taiwan about 200 years ago. It is said to
be the origin of the present-day Taiwanese red alcoholic beverage called Hon-ru-chu that is
popular at festivals and wedding ceremonies [4].
Tofunyu, also called funyu or nyuhu, is a flavored food produced using mold prolifer-
ated on bean cakes which are salted and then matured by soaking in unrefined sake [
8
,
9
].
Fermented bean curd produced using red yeast rice is often called red funyu, and it is said
to have originated the period about 1500 years ago in China. Red funyu is now produced
in Jiangsu, Zhejiang, Sichuan, Hong Kong and Taiwan.
Brewed foods in East Asia were introduced to Japan sometime long ago. Tofuyo, a
type of fermented bean curd (Figure 4), is a fermented food from Okinawa which is similar
to red funyu in China and Taiwan. Tofuyo was introduced to Japan as “a fragrant and
sweet/tasty food that improved digestive function and was effective in the treatment of
various diseases” according to Gyozen Honzo (Edible plants of Okinawa), a book on dietary
plants compiled in 1832 [
4
]. It was highly valued as a nutritional food and side dish in
the 1800s. At present, tofuyo is produced by a novel method using aged sake,awamori
(Okinawan distilled spirit).
Molecules 2021, 26, x FOR PEER REVIEW 5 of 20
Figure 3. Solid-state/liquid-state culture method of red yeast rice.
1.4. Brewed Foods Produced Using Red Yeast Rice
Red yeast rice has been widely used as a material for the production of anchu (Chi-
nese red wine), tofunyu (fermented bean curd), and a coloring agent for foods or a preserva-
tive for meat in China and Taiwan.
The production technique for red Laojiu (Chinese alcohol beverage) originated in a
Fijian Province in China and was introduced into Taiwan about 200 years ago. It is said to
be the origin of the present-day Taiwanese red alcoholic beverage called Hon-ru-chu that
is popular at festivals and wedding ceremonies [4].
Tofunyu, also called funyu or nyuhu, is a flavored food produced using mold prolifer-
ated on bean cakes which are salted and then matured by soaking in unrefined sake [8,9].
Fermented bean curd produced using red yeast rice is often called red funyu, and it is said
to have originated the period about 1500 years ago in China. Red funyu is now produced
in Jiangsu, Zhejiang, Sichuan, Hong Kong and Taiwan.
Brewed foods in East Asia were introduced to Japan sometime long ago. Tofuyo, a
type of fermented bean curd (Figure 4), is a fermented food from Okinawa which is similar
to red funyu in China and Taiwan. Tofuyo was introduced to Japan as “a fragrant and
sweet/tasty food that improved digestive function and was effective in the treatment of
various diseases” according to Gyozen Honzo (Edible plants of Okinawa), a book on dietary
plants compiled in 1832 [4]. It was highly valued as a nutritional food and side dish in the
1800s. At present, tofuyo is produced by a novel method using aged sake, awamori (Okina-
wan distilled spirit).
Figure 4. Tofuyo, a food that has been passed down the generations in Okinawa, Japan.
Funyu has been eaten for more than 1000 years in China. In Japan, it is prepared using
miso produced with red yeast rice. In 1985, a Monuscus fungi was used to brew miso pre-
pared by a traditional method, and it has been in use ever since [10].
Traditional solid-state fermentation method since ancient
Polished rice
Water
Inoculation of Monascus fungi
Sterilization Culture Drying Grinding Product
Liquid-state fermentation method
Culture components
Wat e r
Red yeast rice solution
Product
Jar fermenter Sterilization Culture Sparation
Filtration Concentration Flush heat pasteurization Freeze drying
Inoculation of Monascus fungi
Figure 4. Tofuyo, a food that has been passed down the generations in Okinawa, Japan.
Funyu has been eaten for more than 1000 years in China. In Japan, it is prepared
using miso produced with red yeast rice. In 1985, a Monuscus fungi was used to brew miso
prepared by a traditional method, and it has been in use ever since [10].
Anchu has been produced in Okinawa since the 18th century, according to a written
record and products list [
11
]. For many years, it has been produced in China using yeast rice
on which Monascus fungi are proliferated. During 1850–1900, it is said, red rice and steamed
red rice cakes wrapped in bamboo leaves were a traditional Okinawan food [
12
]. In China,
a book called “Honzo-Jyushin”, published in 1751, described a method for preparing red
rice cake as follows: rice was mixed with red yeast rice and steamed, and the resultant
red rice cake could be offered for food. Red rice is prepared by steaming rice grains after
they have been mixed with red yeast rice. Red rice cakes are prepared by mixing red yeast
rice soaked in sake and mashed in advance. The red yeast rice pigments mentioned above
have been used in processed fish paste products (including crab-flavored fish paste cakes),
jam, tomato ketchup, sweetened bean jam, stewed octopus, salmon roe, and processed
meat products such as ham and sausage. In addition, red yeast rice pigments are used for
coloring bread, confectionaries including rice confectionaries, and beverages, including
amazake, and they are also widely used as pigments for foods in Asia and Europe [6,13].

Molecules 2021,26, 1619 6 of 20
2. Polyketides and Other Metabolites Produced in Monascus Fungi
2.1. Polyketides Identified in Red Yeast Rice
The compendium “Tiangong Kaiwu” describes fish meat as “generally spoilable, but
its quality can be kept by smearing red yeast rice on its surface, even in hot conditions; no
fly or maggot will approach, even 10 days later: red yeast rice is a truly miracle agent”.
This description indicates that red yeast rice has sterilizing or bacteriostatic action to
prevent deterioration of fish meat caused by bacterial contamination (it may prevent fly
swarming by other mechanisms). The custom to use red yeast rice in the preservation of
foods is still used today; it is often used in the preservation of pork and chicken in Taiwan.
Recent studies have demonstrated that M. purpureus produces substances with antibacterial
activity against Bacillus,Streptococcus, and Pseudomonas species. Some of these substances
are considered to be pigments. “Bencao Gangmu” (Compendium Materia Medica, vol. 25)
written by Li Shizhen in 1590 describes a number of medicinal effects of red yeast rice,
including that red yeast rice improves blood circulation, helps digestion, activates splenic
function, cures diarrhea, heals bruises and injuries, enhances blood health, and protects a
woman just after childbirth from blood stasis.
Red yeast rice pigments (polyketides) are called azaphilone pigments, and the fol-
lowing have been isolated and identified: monascin, ankaflavin, and monascinol (yellow
pigments); rubropunctamine and monascorubramine (purple pigments); and rubropunc-
tatin and monascorubrin (red pigments) (Figure 5) [
4
,
7
,
14
]. Furthermore, it has been
reported that red yeast rice produces polyketide derivatives such as monascumic acid
and
γ
-amino butyric acid (GABA) etc. [
15
–
17
]. Monascus pigments are known to have
antibacterial activity and anti-cancer effects and GABA to have blood pressure-regulating
effect [
18
–
20
]. It has also been reported that fermented rice bran with Monascus increases
phenolic acid and enhances antioxidant activity [
21
,
22
]. In addition, organic acids, amino
acids, sterols, decalin compound derivatives, flavonoids, lignans, coumarins, terpenoids,
and polysaccharides are reported as components contained in red yeast rice [23].
Molecules 2021, 26, x FOR PEER REVIEW 7 of 20
Figure 5. Major pigments (polyketides or azaphilone pigments) produced by Monascus fungi.
A potent inhibitor of cholesterol synthesis, monacolin K (lovastatin) was discovered
in 1979 in a strain of Monascus by Endo et al. [1–3,24]. Other active substances with a sim-
ilar structure to monacolin K have since been found (Figure 6) [25,26]. Monacolins have
two forms, acid or lactone form, depending on the conditions of the solution, particularly
the pH (Figure 7) [27].
Figure 6. Monacolins (polyketides) produced by Monascus fungi.
Figure 7. Lactone and acid forms of monacolin K.
Figure 5. Major pigments (polyketides or azaphilone pigments) produced by Monascus fungi.
A potent inhibitor of cholesterol synthesis, monacolin K (lovastatin) was discovered in
1979 in a strain of Monascus by Endo et al. [
1
–
3
,
24
]. Other active substances with a similar
structure to monacolin K have since been found (Figure 6) [
25
,
26
]. Monacolins have two
forms, acid or lactone form, depending on the conditions of the solution, particularly the
pH (Figure 7) [27].

Molecules 2021,26, 1619 7 of 20
Molecules 2021, 26, x FOR PEER REVIEW 7 of 20
Figure 5. Major pigments (polyketides or azaphilone pigments) produced by Monascus fungi.
A potent inhibitor of cholesterol synthesis, monacolin K (lovastatin) was discovered
in 1979 in a strain of Monascus by Endo et al. [1–3,24]. Other active substances with a sim-
ilar structure to monacolin K have since been found (Figure 6) [25,26]. Monacolins have
two forms, acid or lactone form, depending on the conditions of the solution, particularly
the pH (Figure 7) [27].
Figure 6. Monacolins (polyketides) produced by Monascus fungi.
Figure 7. Lactone and acid forms of monacolin K.
Figure 6. Monacolins (polyketides) produced by Monascus fungi.
Molecules 2021, 26, x FOR PEER REVIEW 7 of 20
Figure 5. Major pigments (polyketides or azaphilone pigments) produced by Monascus fungi.
A potent inhibitor of cholesterol synthesis, monacolin K (lovastatin) was discovered
in 1979 in a strain of Monascus by Endo et al. [1–3,24]. Other active substances with a sim-
ilar structure to monacolin K have since been found (Figure 6) [25,26]. Monacolins have
two forms, acid or lactone form, depending on the conditions of the solution, particularly
the pH (Figure 7) [27].
Figure 6. Monacolins (polyketides) produced by Monascus fungi.
Figure 7. Lactone and acid forms of monacolin K.
Figure 7. Lactone and acid forms of monacolin K.
2.2. Production of Metabolites, Including Representative Polyketides in Traditional
Solid-State Fermentation
Endo et al. also studied on red yeast rice that contained natural statins and favored by
the Japanese in their diet. They examined color, taste and fragrance of various red yeast
rice. Useful strains of Monascus fungi were bred, based on productivity of red yeast rice
pigments and monacolin K. Recently, many attempts on breedings of Monascus strains
and production conditions for efficient production of monacolin K have been reported [
28
].
The developed red yeast rice was produced using a traditional solid-state fermentation
method [7].
M. pilosus is frequently used as a health food in Japan; we studied changes in its
metabolite contents during growth. Steam-sterilized rice was inoculated with M. pilosus
NITE BP-412, and a solid-state culture was started when the water content reached 42%.
The culture was grown for 43 days; a temperature of 30
◦
C was used for the first 4 days
and then 22
◦
C for the remaining time; the change in the contents of metabolites was then
analyzed. The change in appearance of the red yeast rice during the 43 days is shown in
Figure 8and demonstrates the gradual change in color of the rice from white to red. The
change in monacolin K content in the red yeast rice during fermentation was measured:
The contents of both the lactone and acid form time-dependently increased (Figure 9). The
contents of three azaphilone pigments (monascin, monascinol, and rubropunctamine) in
red yeast rice were measured: The monascin content reached its peak 20 days after the
start of the culture. Monascinol reached its peak 30 days after the start of the culture,
and rubropunctamine began to increase about 10 days after the start of the culture and
reached its peak at about 30 days. All pigments plateaued after they peaked (Figure 10).
The time course change in the contents of two amino acids (GABA and monascumic acid)
in red yeast rice during fermentation was also examined. The GABA content increased,
with the peak occurring about day 20, and the level gradually decreased thereafter. The

Molecules 2021,26, 1619 8 of 20
monascumic acid content also increased, with the peak on day 20, and the level plateaued
thereafter (Figure 11).
Molecules 2021, 26, x FOR PEER REVIEW 8 of 20
2.2. Production of Metabolites, Including Representative Polyketides in Traditional Solid-State
Fermentation
Endo et al. also studied on red yeast rice that contained natural statins and favored
by the Japanese in their diet. They examined color, taste and fragrance of various red yeast
rice. Useful strains of Monascus fungi were bred, based on productivity of red yeast rice
pigments and monacolin K. Recently, many attempts on breedings of Monascus strains
and production conditions for efficient production of monacolin K have been reported.
[28]. The developed red yeast rice was produced using a traditional solid-state fermenta-
tion method [7].
M. pilosus is frequently used as a health food in Japan; we studied changes in its me-
tabolite contents during growth. Steam-sterilized rice was inoculated with M. pilosus NITE
BP-412, and a solid-state culture was started when the water content reached 42%. The
culture was grown for 43 days; a temperature of 30 °C was used for the first 4 days and
then 22 °C for the remaining time; the change in the contents of metabolites was then
analyzed. The change in appearance of the red yeast rice during the 43 days is shown in
Figure 8 and demonstrates the gradual change in color of the rice from white to red. The
change in monacolin K content in the red yeast rice during fermentation was measured:
The contents of both the lactone and acid form time-dependently increased (Figure 9). The
contents of three azaphilone pigments (monascin, monascinol, and rubropunctamine) in
red yeast rice were measured: The monascin content reached its peak 20 days after the
start of the culture. Monascinol reached its peak 30 days after the start of the culture, and
rubropunctamine began to increase about 10 days after the start of the culture and reached
its peak at about 30 days. All pigments plateaued after they peaked (Figure 10). The time
course change in the contents of two amino acids (GABA and monascumic acid) in red
yeast rice during fermentation was also examined. The GABA content increased, with the
peak occurring about day 20, and the level gradually decreased thereafter. The monas-
cumic acid content also increased, with the peak on day 20, and the level plateaued there-
after (Figure 11).
Figure 8. Time course change in appearance of red koji, which reddens during fermentation.
Figure 8. Time course change in appearance of red koji, which reddens during fermentation.
Molecules 2021, 26, x FOR PEER REVIEW 9 of 20
Figure 9. Time course change in the content of lactone form and acid form of monacolin K in red
yeast rice during fermentation, quantified using the method specified by the Korea Food and Drug
Administration (KFDA) [29].
Figure 10. Time course change in the contents of 3 azaphilone pigments in red yeast rice during
fermentation, quantified according to the reference method [30].
0
100
200
300
400
135791113151719212325272931333537394143
Concentration (mg/100 g)
Days in culture
monacolin K lactone
0
100
200
300
400
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43
Concentration (mg/100 g)
Days in culture
monacolin K hydroxyl acid
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
absorbance at 391 nm
Days in culture
monascin
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
Absorbance at 388 nm
Days in culture
monascinol
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
Absorbance at 538 nm
Days in culture
rubropunctamine
10×106
8×106
4×106
0
10×106
8×106
4×106
0
10×106
8×106
4×106
0
Figure 9.
Time course change in the content of lactone form and acid form of monacolin K in red
yeast rice during fermentation, quantified using the method specified by the Korea Food and Drug
Administration (KFDA) [29].

Molecules 2021,26, 1619 9 of 20
Molecules 2021, 26, x FOR PEER REVIEW 9 of 20
Figure 9. Time course change in the content of lactone form and acid form of monacolin K in red
yeast rice during fermentation, quantified using the method specified by the Korea Food and Drug
Administration (KFDA) [29].
Figure 10. Time course change in the contents of 3 azaphilone pigments in red yeast rice during
fermentation, quantified according to the reference method [30].
0
100
200
300
400
135791113151719212325272931333537394143
Concentration (mg/100 g)
Days in culture
monacolin K lactone
0
100
200
300
400
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43
Concentration (mg/100 g)
Days in culture
monacolin K hydroxyl acid
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
absorbance at 391 nm
Days in culture
monascin
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
Absorbance at 388 nm
Days in culture
monascinol
0.E+00
4.E+06
8.E+06
1.E+07
1 3 5 7 9 1113151719212325272931333537394143
Absorbance at 538 nm
Days in culture
rubropunctamine
10×106
8×106
4×106
0
10×106
8×106
4×106
0
10×106
8×106
4×106
0
Figure 10.
Time course change in the contents of 3 azaphilone pigments in red yeast rice during
fermentation, quantified according to the reference method [30].
Molecules 2021, 26, x FOR PEER REVIEW 10 of 20
Figure 11. Time course change in the contents of 2 amino acids (GABA and monascumic acid) in
red yeast rice during fermentation, quantified by liquid chromatography-mass spectrometry (LC-
MS) [16,17].
The results suggest that M. pilosus fought against foreign enemies, utilizing monas-
cumic acid as its antibacterial activity in the first half of their growth and monacolin K
with its cholesterol synthesis inhibiting activity in the second half of their growth. GABA
could be used as a nitrogen source in the second half of growth, when nutrients become
deficient; however, we suggest GABA was mainly used to fight against foreign enemies
since it decreased in the middle of the second half of the growth phase. Based on these
findings, we expect further improvements to traditional solid-state fermentation methods
will lead to the development of useful materials in the production of red yeast rice.
3. Effectiveness of Red Yeast Rice: Its Functional Ingredients and Physiological Ac-
tions on Lipid Metabolism and the Circulatory System
3.1. Monacolins and Their Cholesterol Lowering Effect
Monacolins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reduc-
tase, a key enzyme regulating hepatic cholesterol synthesis, and exert potent serum cho-
lesterol lowering effects (Figure 12).
Figure 12. Biosynthetic pathway of cholesterol synthesis and the action of red yeast rice in it.
Lovastatin and its analogs (including their derivatives) have been used as medicines
since 1987 by Japanese and foreign pharmaceutical companies. Statins inhibit HMG-CoA
reductase, lower hepatic cholesterol biosynthesis and elevate the expression of hepatic
LDL-receptors to maintain cholesterol homeostasis, which in turn enhances uptake of
LDL-cholesterol into the liver and decreases blood cholesterol levels [31–33]. LDL-choles-
terol is known as bad cholesterol because it is involved in atheroma formation and causes
atherosclerosis. Since statins have excellent LDL-cholesterol-lowering effects, they are
used as first-line drugs for patients with hypercholesterolemia, and several world-wide
large-scale clinical trials have been conducted on statins. These trials have demonstrated
0.E+00
2.E+08
3.E+08
135791113151719212325272931333537394143
Intensity
(m/z = [M+H]+:216.25)
Days in culture
monascumic acid
0.E+00
1.E+07
2.E+07
135791113151719212325272931333537394143
Intensity
(m/z = [M+H]+:104.12)
Days in culture
GABA
3×10
8
2×10
8
2×10
7
1×10
7
0
0
Acetyl CoA HMG-CoA Mevalonic acid Squalene Lanosterol
Cholesterol
HMG-CoA reductase
Red yeast rice
×
Figure 11.
Time course change in the contents of 2 amino acids (GABA and monascumic acid)
in red yeast rice during fermentation, quantified by liquid chromatography-mass spectrometry
(LC-MS) [16,17].
The results suggest that M. pilosus fought against foreign enemies, utilizing monascumic
acid as its antibacterial activity in the first half of their growth and monacolin K with its
cholesterol synthesis inhibiting activity in the second half of their growth. GABA could be
used as a nitrogen source in the second half of growth, when nutrients become deficient;

Molecules 2021,26, 1619 10 of 20
however, we suggest GABA was mainly used to fight against foreign enemies since it
decreased in the middle of the second half of the growth phase. Based on these findings,
we expect further improvements to traditional solid-state fermentation methods will lead
to the development of useful materials in the production of red yeast rice.
3. Effectiveness of Red Yeast Rice: Its Functional Ingredients and Physiological
Actions on Lipid Metabolism and the Circulatory System
3.1. Monacolins and Their Cholesterol Lowering Effect
Monacolins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase,
a key enzyme regulating hepatic cholesterol synthesis, and exert potent serum cholesterol
lowering effects (Figure 12).
Molecules 2021, 26, x FOR PEER REVIEW 10 of 20
Figure 11. Time course change in the contents of 2 amino acids (GABA and monascumic acid) in
red yeast rice during fermentation, quantified by liquid chromatography-mass spectrometry (LC-
MS) [16,17].
The results suggest that M. pilosus fought against foreign enemies, utilizing monas-
cumic acid as its antibacterial activity in the first half of their growth and monacolin K
with its cholesterol synthesis inhibiting activity in the second half of their growth. GABA
could be used as a nitrogen source in the second half of growth, when nutrients become
deficient; however, we suggest GABA was mainly used to fight against foreign enemies
since it decreased in the middle of the second half of the growth phase. Based on these
findings, we expect further improvements to traditional solid-state fermentation methods
will lead to the development of useful materials in the production of red yeast rice.
3. Effectiveness of Red Yeast Rice: Its Functional Ingredients and Physiological Ac-
tions on Lipid Metabolism and the Circulatory System
3.1. Monacolins and Their Cholesterol Lowering Effect
Monacolins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reduc-
tase, a key enzyme regulating hepatic cholesterol synthesis, and exert potent serum cho-
lesterol lowering effects (Figure 12).
Figure 12. Biosynthetic pathway of cholesterol synthesis and the action of red yeast rice in it.
Lovastatin and its analogs (including their derivatives) have been used as medicines
since 1987 by Japanese and foreign pharmaceutical companies. Statins inhibit HMG-CoA
reductase, lower hepatic cholesterol biosynthesis and elevate the expression of hepatic
LDL-receptors to maintain cholesterol homeostasis, which in turn enhances uptake of
LDL-cholesterol into the liver and decreases blood cholesterol levels [31–33]. LDL-choles-
terol is known as bad cholesterol because it is involved in atheroma formation and causes
atherosclerosis. Since statins have excellent LDL-cholesterol-lowering effects, they are
used as first-line drugs for patients with hypercholesterolemia, and several world-wide
large-scale clinical trials have been conducted on statins. These trials have demonstrated
0.E+00
2.E+08
3.E+08
135791113151719212325272931333537394143
Intensity
(m/z = [M+H]+:216.25)
Days in culture
monascumic acid
0.E+00
1.E+07
2.E+07
135791113151719212325272931333537394143
Intensity
(m/z = [M+H]+:104.12)
Days in culture
GABA
3×10
8
2×10
8
2×10
7
1×10
7
0
0
Acetyl CoA HMG-CoA Mevalonic acid Squalene Lanosterol
Cholesterol
HMG-CoA reductase
Red yeast rice
×
Figure 12. Biosynthetic pathway of cholesterol synthesis and the action of red yeast rice in it.
Lovastatin and its analogs (including their derivatives) have been used as medicines
since 1987 by Japanese and foreign pharmaceutical companies. Statins inhibit HMG-CoA
reductase, lower hepatic cholesterol biosynthesis and elevate the expression of hepatic
LDL-receptors to maintain cholesterol homeostasis, which in turn enhances uptake of LDL-
cholesterol into the liver and decreases blood cholesterol levels [
31
–
33
]. LDL-cholesterol
is known as bad cholesterol because it is involved in atheroma formation and causes
atherosclerosis. Since statins have excellent LDL-cholesterol-lowering effects, they are used
as first-line drugs for patients with hypercholesterolemia, and several world-wide large-
scale clinical trials have been conducted on statins. These trials have demonstrated not only
their efficacy on cardiovascular disease such as cardiac infarction and cerebral stroke but
also various actions such as potential preventive action on bone fracture. Statins prevented
cardiovascular events by 25–30% in clinical trials assessing primary and secondary pre-
ventive effects on coronary artery disease, indicating that they are essential medicines for
patients with cardiovascular disease [
34
,
35
]. Since it has been reported recently that statins
show pleiotropic effects, such as a restorative effect on vascular endothelial functions and
anti-inflammatory effects, an accumulation of evidence for their therapeutic and preventive
effects on various diseases is expected [36,37].
Clinical studies in Japan have also been conducted on processed food containing red yeast
rice produced using the traditional solid-state fermentation described in Section 2.2 [38–40].
In normal healthy volunteers with plasma LDL-cholesterol levels of 120 mg/dL or
higher, long-term feeding of a processed food product containing 100 or 200 mg of red
yeast rice produced by solid-state fermentation significantly lowered plasma levels of
LDL-cholesterol and total cholesterol compared to those in volunteers fed the placebo at
2–8 weeks
after starting the feeding. The lowered levels returned to the initial values after
the end of red yeast rice intake. No significant differences in HDL-cholesterol and triglyc-
eride levels and safety evaluation items among the 3 groups were found
(Figure 13) [38]
.
In addition, in patients with hyperlipidemia where it was not improved during 1-month-
diet therapy according to an NCEP panel, repetitive intake of a processed food product
containing red yeast rice at 1 g/day significantly lowered levels of total cholesterol and
LDL-cholesterol by about 10% [
40
]. Reports of clinical trials in Europe also show significant
improvements in hypercholesterolemia by ingestion of red yeast rice containing 3–10 mg
of monacolin K [41,42].

Molecules 2021,26, 1619 11 of 20
Molecules 2021, 26, x FOR PEER REVIEW 11 of 20
not only their efficacy on cardiovascular disease such as cardiac infarction and cerebral
stroke but also various actions such as potential preventive action on bone fracture. Statins
prevented cardiovascular events by 25–30% in clinical trials assessing primary and sec-
ondary preventive effects on coronary artery disease, indicating that they are essential
medicines for patients with cardiovascular disease [34,35]. Since it has been reported re-
cently that statins show pleiotropic effects, such as a restorative effect on vascular endo-
thelial functions and anti-inflammatory effects, an accumulation of evidence for their ther-
apeutic and preventive effects on various diseases is expected [36,37].
Clinical studies in Japan have also been conducted on processed food containing red
yeast rice produced using the traditional solid-state fermentation described in Section 2.2.
[38–40].
In normal healthy volunteers with plasma LDL-cholesterol levels of 120 mg/dL or
higher, long-term feeding of a processed food product containing 100 or 200 mg of red
yeast rice produced by solid-state fermentation significantly lowered plasma levels of
LDL-cholesterol and total cholesterol compared to those in volunteers fed the placebo at
2–8 weeks after starting the feeding. The lowered levels returned to the initial values after
the end of red yeast rice intake. No significant differences in HDL-cholesterol and triglyc-
eride levels and safety evaluation items among the 3 groups were found (Figure 13) [38].
In addition, in patients with hyperlipidemia where it was not improved during 1-month-
diet therapy according to an NCEP panel, repetitive intake of a processed food product
containing red yeast rice at 1 g/day significantly lowered levels of total cholesterol and
LDL-cholesterol by about 10% [40]. Reports of clinical trials in Europe also show signifi-
cant improvements in hypercholesterolemia by ingestion of red yeast rice containing 3-10
mg of monacolin K [41,42].
Figure 13. Effect of intake of red yeast rice produced by solid-state fermentation in normal healthy
volunteers whose plasma cholesterol levels were 120 mg/dL or higher. Each bar indicates the
mean ± standard deviation. *: Significant difference from start of ingestion (p < 0.05, paired
ANOVA). #: Significantly different from the placebo group (p < 0.05, multiple comparison using
Bonferroni).
Recently, we compared the pharmacokinetics of monacolin K in blood after oral ad-
ministration of purified monacolin K (lactone form, 99% purity) and red yeast rice pro-
duced by solid-state fermentation in male SD rats (7 weeks old). Most of the monacolin K
in the plasma was detected in its acid form: both in the monacolin K-administered group
and the red yeast rice -administered group. Surprisingly, the maximum level (C max) and
area under curve (AUC) of plasma monacolin K concentration 4 hours after administra-
Figure 13.
Effect of intake of red yeast rice produced by solid-state fermentation in normal healthy
volunteers whose plasma cholesterol levels were 120 mg/dL or higher. Each bar indicates the
mean ±standard
deviation. *: Significant difference from start of ingestion (p< 0.05, paired ANOVA).
#: Significantly different from the placebo group (p< 0.05, multiple comparison using Bonferroni).
Recently, we compared the pharmacokinetics of monacolin K in blood after oral
administration of purified monacolin K (lactone form, 99% purity) and red yeast rice
produced by solid-state fermentation in male SD rats (7 weeks old). Most of the monacolin
K in the plasma was detected in its acid form: both in the monacolin K-administered group
and the red yeast rice -administered group. Surprisingly, the maximum level (C max) and
area under curve (AUC) of plasma monacolin K concentration 4 hours after administration
were several times higher in the red yeast rice-administered group than in the purified
monacolin K-administered group (Figure 14, Table 3). These results suggest that red yeast
rice contains ingredients that enhance the absorption of monacolin K into blood. The
medicinal benefit of red yeast rice is considered to be different to that of monacolin K
alone. Furthermore, our recent experiments show that monacolin L, monascinol, and
monascodilone also have HMG-CoA reductase activity. Since red yeast rice contains
various ingredients, synergistic effects are expected.
Molecules 2021, 26, x FOR PEER REVIEW 12 of 20
tion were several times higher in the red yeast rice-administered group than in the puri-
fied monacolin K-administered group (Figure 14, Table 3). These results suggest that red
yeast rice contains ingredients that enhance the absorption of monacolin K into blood. The
medicinal benefit of red yeast rice is considered to be different to that of monacolin K
alone. Furthermore, our recent experiments show that monacolin L, monascinol, and
monascodilone also have HMG-CoA reductase activity. Since red yeast rice contains var-
ious ingredients, synergistic effects are expected.
Figure 14. Plasma concentrations of lactone form and acid form of monacolin K after single administration of purified
monacolin K or red yeast rice (40 mg/kg monacolin K or dose of red yeast rice equivalent to 40 mg/kg monacolin K) in
male SD rats (7 weeks old). Each bar indicates the mean ± standard deviation, quantified according to the reference method
[43].
Table 3. Pharmacokinetic parameters of the lactone form and acid form of monacolin K in plasma after single administra-
tion of purified monacolin K or red yeast rice (40 mg/kg monacolin K or dose of red yeast rice equivalent to 40 mg/kg
monacolin K). Peak analysis was performed according to the reference method [44].
PK parameter of Monacolin K Lactone PK Parameter Of Monacolin K Hydroxy Acid
Monacolin K Administration Group Monacolin K Administration Group
PK Parameter 101 102 103 Mean S.D. PK Parameter 101 102 103 Mean S.D.
t1/2(h) N.C. N.C. N.C. - - t1/2(h) 2.7 1.7 N.C. 2.2 -
Tmax(h) 1.0 1.0 N.C. 1.0 - Tmax(h) 1.0 1.0 2.0 1.3 0.6
Cmax(ng/ml) 3.11 1.85 N.C. 2.48 - Cmax(ng/ml) 72.6 113 55.5 80.4 29.5
AUC0-4h(ng·h/ml) 3.11 1.85 N.C. 2.48 - AUC0-4h(ng·h/ml) 143 274 153 190 73
Red yeast rice administration group Red yeast rice administration group
PK parameter 201 202 203 Mean S.D. PK parameter 201 202 203 Mean S.D.
t1/2(h) N.C. N.C. N.C. - - t1/2(h) 1.4 1.1 0.98 1.1 0.2
Tmax(h) 1.0 1.0 1.0 1.0 0.0 Tmax(h) 1.0 1.0 1.0 1.0 0.0
Cmax(ng/ml) 4.32 4.03 3.54 3.96 0.39 Cmax(ng/ml) 254 349 406 336 77
AUC0-4h(ng·h/ml) 7.20 5.22 6.46 6.29 1.00 AUC0-4h(ng·h/ml) 457 470 632 520 98
S.D.: Standard deviation
3.2. Improving Effects of Red Yeast Rice on Chyle in Blood and Increased Viscosity Caused by
Hyperlipidemia
In general, continuous intake of a high-fat or high-cholesterol diet causes hyper-
lipidemia and the blood develops chyle, a white cloudy substance which mainly consists
of lipoproteins. Chylemia is regarded as a risk factor for circulatory diseases, and its sup-
pression is considered to be important for risk reduction. Recently, we conducted an ex-
periment in which male Japanese white rabbits (10–12 weeks old) were fed a diet contain-
ing 0.25% cholesterol for 2 weeks to produce chylemia. The rabbits were then allocated
0.0
1.0
2.0
3.0
4.0
5.0
6.0
01234
Monacolin K lactone concentration
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
450.0
01234
Monacolin K hydroxy acid concentration
Concentration (ng/ml)
Time (h)
Concentration (ng/ml)
Time (h)
Monacolin K group (n=3)
Red yeast rice group (n=3)
Monacolin K group (n=3)
Red yeast rice group (n=3)
Figure 14.
Plasma concentrations of lactone form and acid form of monacolin K after single administration of purified
monacolin K or red yeast rice (40 mg/kg monacolin K or dose of red yeast rice equivalent to 40 mg/kg monacolin K) in male
SD rats (7 weeks old). Each bar indicates the mean
±
standard deviation, quantified according to the reference method [
43
].

Molecules 2021,26, 1619 12 of 20
Table 3.
Pharmacokinetic parameters of the lactone form and acid form of monacolin K in plasma after single administration of
purified monacolin K or red yeast rice (40 mg/kg monacolin K or dose of red yeast rice equivalent to 40 mg/kg monacolin K).
Peak analysis was performed according to the reference method [44].
PK Parameter of Monacolin K Lactone PK Parameter Of Monacolin K Hydroxy Acid
Monacolin K Administration Group Monacolin K Administration Group
PK Parameter 101 102 103 Mean S.D. PK Parameter 101 102 103 Mean S.D.
t1/2 (h) N.C. N.C. N.C. - - t1/2 (h) 2.7 1.7 N.C. 2.2 -
Tmax (h) 1.0 1.0 N.C. 1.0 - Tmax (h) 1.0 1.0 2.0 1.3 0.6
Cmax (ng/mL) 3.11 1.85 N.C. 2.48 - Cmax (ng/mL) 72.6 113 55.5 80.4 29.5
AUC0–4h (ng·h/mL) 3.11 1.85 N.C. 2.48 - AUC0–4h (ng·h/mL) 143 274 153 190 73
Red yeast rice administration group Red yeast rice administration group
PK parameter 201 202 203 Mean S.D. PK parameter 201 202 203 Mean S.D.
t1/2 (h) N.C. N.C. N.C. - - t1/2 (h) 1.4 1.1 0.98 1.1 0.2
Tmax (h) 1.0 1.0 1.0 1.0 0.0 Tmax (h) 1.0 1.0 1.0 1.0 0.0
Cmax (ng/mL) 4.32 4.03 3.54 3.96 0.39 Cmax (ng/mL) 254 349 406 336 77
AUC0–4h (ng·h/mL) 7.20 5.22 6.46 6.29 1.00 AUC0–4h (ng·h/mL) 457 470 632 520 98
S.D.: Standard deviation
3.2. Improving Effects of Red Yeast Rice on Chyle in Blood and Increased Viscosity Caused
by Hyperlipidemia
In general, continuous intake of a high-fat or high-cholesterol diet causes hyperlipi-
demia and the blood develops chyle, a white cloudy substance which mainly consists of
lipoproteins. Chylemia is regarded as a risk factor for circulatory diseases, and its suppres-
sion is considered to be important for risk reduction. Recently, we conducted an experiment
in which male Japanese white rabbits (10–12 weeks old) were fed a diet containing 0.25%
cholesterol for 2 weeks to produce chylemia. The rabbits were then allocated into a red
yeast rice-treated group, in which powdered red yeast rice was orally administered for
3 weeks or non-treated group. Blood samples were collected from both groups for plasma
biochemical examinations and measurement of plasma turbidity. Macroscopic observations
showed lower plasma turbidity in the red yeast rice-treated group compared with the
non-treated group, and biochemical analysis revealed a statistically significant increase in
light transmittance (Figure 15) and decrease in plasma total cholesterol levels in the red
yeast rice-treated group compared with the non-treated group.
Molecules 2021, 26, x FOR PEER REVIEW 13 of 20
into a red yeast rice-treated group, in which powdered red yeast rice was orally adminis-
tered for 3 weeks or non-treated group. Blood samples were collected from both groups
for plasma biochemical examinations and measurement of plasma turbidity. Macroscopic
observations showed lower plasma turbidity in the red yeast rice-treated group compared
with the non-treated group, and biochemical analysis revealed a statistically significant
increase in light transmittance (Figure 15) and decrease in plasma total cholesterol levels
in the red yeast rice-treated group compared with the non-treated group.
Figure 15. Difference in transmittance of plasma between red yeast rice-treated (2 weeks) and non-
treated groups of male Japanese white rabbits (10–12 weeks old) fed a high-cholesterol diet. A
decrease in turbidity in the red yeast rice-treated group is apparent. Each bar indicates the mean ±
standard deviation. Significant differences were tested by Student's t-test. Plasma cloudiness was
evaluated by measuring the transmittance at a wavelength of 660 nm using an absorptiometer.
It has also been reported that hyperlipidemia induces metabolic abnormality of lipo-
proteins and an increase in plasma viscosity, which in turn elevates the risk of cardiac and
cerebrovascular diseases [45–47]. Lovastatin or ezetimibe, anti-hyperlipidemic drugs,
have been reported to decrease plasma viscosity [48,49]. In our study, male Japanese white
rabbits (14 weeks old) were fed a diet containing 0.25% cholesterol (HC diet) for 3 months
as a hyperlipidemic animal model. During the 3-month feeding period, the control group
was fed the HC diet alone, and the red yeast rice-treated group was fed the HC diet with
red yeast rice at 500 mg/kg body weight. Blood biochemical analyses, performed during
the feeding period, included measurements of plasma turbidity, viscosity and cholesterol
content of lipoproteins. Plasma turbidity was improved, and total cholesterol and LDL-
cholesterol plasma levels were reduced in the red yeast rice-treated group between
months 1–3 of the experimental period, when compared to the control group. Further-
more, 3 months after the start of administration, the low-density cholesterol content of
lipoproteins and plasma viscosity were still lower in the red yeast rice-treated group com-
pared with the control group (Figure 16). In particular, the cholesterol contents in chylo-
microns and VLDL were significantly lowered (Figure 17). These results indicate that in-
gredients in red yeast rice suppressed the increase in plasma viscosity by decreasing the
content of large (low-density) lipoproteins through a reduction in VLDL release and clear-
ance of chylomicrons.
Figure 15.
Difference in transmittance of plasma between red yeast rice-treated (2 weeks) and
non-treated groups of male Japanese white rabbits (10–12 weeks old) fed a high-cholesterol diet.
A decrease in turbidity in the red yeast rice-treated group is apparent. Each bar indicates the
mean ±standard
deviation. Significant differences were tested by Student’s t-test. Plasma cloudiness
was evaluated by measuring the transmittance at a wavelength of 660 nm using an absorptiometer.
It has also been reported that hyperlipidemia induces metabolic abnormality of
lipoproteins and an increase in plasma viscosity, which in turn elevates the risk of cardiac

Molecules 2021,26, 1619 13 of 20
and cerebrovascular diseases [
45
–
47
]. Lovastatin or ezetimibe, anti-hyperlipidemic drugs,
have been reported to decrease plasma viscosity [
48
,
49
]. In our study, male Japanese
white rabbits (14 weeks old) were fed a diet containing 0.25% cholesterol (HC diet) for
3 months as a hyperlipidemic animal model. During the 3-month feeding period, the
control group was fed the HC diet alone, and the red yeast rice-treated group was fed
the HC diet with red yeast rice at 500 mg/kg body weight. Blood biochemical analyses,
performed during the feeding period, included measurements of plasma turbidity, vis-
cosity and cholesterol content of lipoproteins. Plasma turbidity was improved, and total
cholesterol and LDL-cholesterol plasma levels were reduced in the red yeast rice-treated
group between months 1–3 of the experimental period, when compared to the control
group. Furthermore, 3 months after the start of administration, the low-density cholesterol
content of lipoproteins and plasma viscosity were still lower in the red yeast rice-treated
group compared with the control group (Figure 16). In particular, the cholesterol contents
in chylomicrons and VLDL were significantly lowered (Figure 17). These results indicate
that ingredients in red yeast rice suppressed the increase in plasma viscosity by decreasing
the content of large (low-density) lipoproteins through a reduction in VLDL release and
clearance of chylomicrons.
Molecules 2021, 26, x FOR PEER REVIEW 14 of 20
Figure 16. Time course changes in plasma viscosity in a control group and a red yeast rice-treated
group in hypercholesterolemic model rabbits. Each bar indicates the mean ± standard deviation.
Significant differences between control group and red yeast group were tested by Student's t-test
(#: p < 0.05, ##: p < 0.01). Plasma viscosity was measured using a plate and cone viscometer accord-
ing to the reference method [50].
Figure 17. Time course change in contents of cholesterol in plasma low-density lipoproteins (chylomicron-cholesterol and
VLDL-cholesterol) obtained from a red yeast rice-treated and control groups of hypercholesteremic model rabbits. Each
bar indicates the mean ± standard deviation. Significant differences between control group and red yeast group were
tested by Student's t-test (##: p < 0.01). Plasma lipoprotein cholesterol was quantified according to the reference method
[51].
Red yeast rice has the potential to prevent vascular disease associated with hyper-
lipidemia or reduce the risk for these diseases, through suppression of atheroma for-
mation and improve blood fluidity, by lowering levels of chylomicrons and VLDL, lipo-
proteins that are the main components of plasma chyle.
3.3. Promising Effects of Ingredients in Red Yeast Rice on Risk Reduction for Circulatory
Diseases
The evidence presented above suggests red yeast rice could reduce the risk of vascu-
lar diseases associated with hyperlipidemia; however, red yeast rice also contain statins
and various other ingredients which are effective in the circulatory system. Table 4 sum-
marizes the potential effects of monacolin K (lovastatin) on circulatory diseases, including
cardiac disease. There has been a lot of evidence reported on the favorable actions of
1.30
1.32
1.34
1.36
1.38
1.40
1.42
1.44
1.46
1.48
1.50
04812
Control group Red yeast rice group
Time (weeks)
Plasma viscosity (cp)
#
##
0
10
20
30
40
50
60
70
80
04812
Control group Red yeast rice group
CM-C (mg/dL)
Time (weeks)
##
##
##
0
50
100
150
200
250
300
04812
Control group Red yeast rice group
VLDL-C (mg/dL)
Time (weeks)
##
##
##
Figure 16.
Time course changes in plasma viscosity in a control group and a red yeast rice-treated
group in hypercholesterolemic model rabbits. Each bar indicates the mean
±
standard deviation.
Significant differences between control group and red yeast group were tested by Student’s t-test (#:
p< 0.05, ##: p< 0.01). Plasma viscosity was measured using a plate and cone viscometer according to
the reference method [50].
Molecules 2021, 26, x FOR PEER REVIEW 14 of 20
Figure 16. Time course changes in plasma viscosity in a control group and a red yeast rice-treated
group in hypercholesterolemic model rabbits. Each bar indicates the mean ± standard deviation.
Significant differences between control group and red yeast group were tested by Student's t-test
(#: p < 0.05, ##: p < 0.01). Plasma viscosity was measured using a plate and cone viscometer accord-
ing to the reference method [50].
Figure 17. Time course change in contents of cholesterol in plasma low-density lipoproteins (chylomicron-cholesterol and
VLDL-cholesterol) obtained from a red yeast rice-treated and control groups of hypercholesteremic model rabbits. Each
bar indicates the mean ± standard deviation. Significant differences between control group and red yeast group were
tested by Student's t-test (##: p < 0.01). Plasma lipoprotein cholesterol was quantified according to the reference method
[51].
Red yeast rice has the potential to prevent vascular disease associated with hyper-
lipidemia or reduce the risk for these diseases, through suppression of atheroma for-
mation and improve blood fluidity, by lowering levels of chylomicrons and VLDL, lipo-
proteins that are the main components of plasma chyle.
3.3. Promising Effects of Ingredients in Red Yeast Rice on Risk Reduction for Circulatory
Diseases
The evidence presented above suggests red yeast rice could reduce the risk of vascu-
lar diseases associated with hyperlipidemia; however, red yeast rice also contain statins
and various other ingredients which are effective in the circulatory system. Table 4 sum-
marizes the potential effects of monacolin K (lovastatin) on circulatory diseases, including
cardiac disease. There has been a lot of evidence reported on the favorable actions of
1.30
1.32
1.34
1.36
1.38
1.40
1.42
1.44
1.46
1.48
1.50
04812
Control group Red yeast rice group
Time (weeks)
Plasma viscosity (cp)
#
##
0
10
20
30
40
50
60
70
80
04812
Control group Red yeast rice group
CM-C (mg/dL)
Time (weeks)
##
##
##
0
50
100
150
200
250
300
04812
Control group Red yeast rice group
VLDL-C (mg/dL)
Time (weeks)
##
##
##
Figure 17. Time course change in contents of cholesterol in plasma low-density lipoproteins (chylomicron-cholesterol and
VLDL-cholesterol) obtained from a red yeast rice-treated and control groups of hypercholesteremic model rabbits. Each bar
indicates the mean
±
standard deviation. Significant differences between control group and red yeast group were tested by
Student’s t-test (##: p< 0.01). Plasma lipoprotein cholesterol was quantified according to the reference method [51].

Molecules 2021,26, 1619 14 of 20
Red yeast rice has the potential to prevent vascular disease associated with hyperlipi-
demia or reduce the risk for these diseases, through suppression of atheroma formation
and improve blood fluidity, by lowering levels of chylomicrons and VLDL, lipoproteins
that are the main components of plasma chyle.
3.3. Promising Effects of Ingredients in Red Yeast Rice on Risk Reduction for Circulatory Diseases
The evidence presented above suggests red yeast rice could reduce the risk of vascular
diseases associated with hyperlipidemia; however, red yeast rice also contain statins and
various other ingredients which are effective in the circulatory system. Table 4summarizes
the potential effects of monacolin K (lovastatin) on circulatory diseases, including cardiac
disease. There has been a lot of evidence reported on the favorable actions of statins, includ-
ing their HMG-CoA reductase inhibiting activity which suppresses atheroma formation
in atherosclerosis [
52
–
54
], improving effects on blood circulation [
55
,
56
], and pleiotropic
effects on nitric oxide (NO) production which plays a pivotal role in homeostasis of the
cardiovascular system and the NO synthetase–NO pathway [
57
–
59
]. Effects of lovastatin
on atherogenic signaling cascades [
60
] have also been reported [
61
–
63
]. There have also
been similar favorable reports of red yeast rice extracts, such as upregulation of constitutive
NO synthetase expression, the increase in plasma levels of nitric oxides and improvement
of abnormal hemorheology in an atherosclerotic rat model induced by high-cholesterol diet
feeding [
64
]. These effects are considered to be beneficial in the prevention of circulatory
diseases and improvement in blood circulation.
Table 4. Actions of monacolin K (lovastatin) on circulatory system and related fields.
Evaluation Target Study Subjects or Study Materials Effect of Monacolin K Ref.
Atheroma formation
Rabbits fed on a high-lipid diet Decrease in number of plaques in the aorta and
lung artery [52]
Patients with hypercholesterolemia
Inhibition of platelet aggregation, macrophage foam
cell formation and LDL oxidation [53]
Human umbilical vein endothelial
cells (HUVECs) Inhibition of NF-KB activation by CRP [54]
Blood circulation
Hypertensive model mice Increase in renal blood flow [55]
Several studies using
experimental animals
Increase in cerebral blood flow and cerebral
vasomotor response [56]
NOS signaling
pathway
Cardiac myocytes
Increase of IL-1 induced production of nitrite
(Increase in NOS expression and NO production
mediated by Rho inhibition)
[61]
Squamous epithelial cancer cells Induction of expression of Rho family proteins [62]
Mesenchymal stem cells derived from
rat bone marrow
Activation (phosphorylation) of AI3K/Akt pathway
and MEK 1/2 pathway [63]
Ingredients that are known to be effective in red yeast rice, other than statins, include
GABA, which exerts a hypotensive effect through reduction of adrenergic vasoconstriction
by its suppressive effect on the release of sympathetic nerve transmitters mediated by
presynaptic GABA receptors [
65
,
66
]. In addition, GABA promotes sodium excretion from
the kidneys and suppresses increases in blood pressure [67,68].
Oxidative stress is also regarded as a therapeutic target related to atherosclerosis.
Reactive oxygen inactivates NO and at the same time damages vascular endothelial cells
and reduces NO production. It has also been suggested that plasma LDL suppresses NOS
activity in vascular endothelial cells by hydroxyl radicals and the like, thereby reducing
NO production and promoting arteriosclerosis. [
69
,
70
]. Lovastatin inhibits oxidation of
LDL, and this improves the vascular endothelial function (vasoconstrictor reaction) in
hyperlipidemia, and in particular, the combined use of an antioxidant can significantly

Molecules 2021,26, 1619 15 of 20
improve the function [
64
,
71
]. Antioxidant activity has also been reported in red yeast rice
pigments [
72
,
73
]: monascin and ankaflavin suppressed LDL-cholesterol oxidation [
74
]. In
addition, a previous clinical study reported that a red yeast rice extract reduced plasma
levels of oxidized LDL, an index of oxidative stress, and lipoprotein-associated phospholi-
pase A
2
activity [
75
]. Red yeast rice made from brown rice, black rice, and red rice has also
been shown to improve vascular endothelial function with increased NO production [76].
Monascin and ankaflavin are reported to act as the agonist for peroxisome proliferator-
activated receptors (PPARs), e.g., PPAR
α
[
77
]. PPARs that are involved in metabolism of
carbohydrates, lipids, and energy are also closely involved in development of life-style
related diseases, such as obesity and atherosclerosis. PPAR
α
agonists (fibrates) have been
clinically used as antihyperlipidemic drugs.
Vascular function can be improved by increasing NO, suppressing oxidative stress,
hypertension, obesity, etc. [
78
–
80
]. It is expected that ingredients contained in red yeast
rice, such as monacolin K (lovastatin), GABA, and red yeast rice pigments (azaphilone
pigments) exert synergic or additive effects to lower the risk for atherosclerosis and other
circulatory diseases (Figure 18).
Molecules 2021, 26, x FOR PEER REVIEW 16 of 20
related diseases, such as obesity and atherosclerosis. PPARα agonists (fibrates) have been
clinically used as antihyperlipidemic drugs.
Vascular function can be improved by increasing NO, suppressing oxidative stress,
hypertension, obesity, etc. [78–80]. It is expected that ingredients contained in red yeast
rice, such as monacolin K (lovastatin), GABA, and red yeast rice pigments (azaphilone
pigments) exert synergic or additive effects to lower the risk for atherosclerosis and other
circulatory diseases (Figure 18).
Figure 18. Expected effect on the circulatory system of red yeast rice and its components.
4. Safety of Red Yeast Rice
Red yeast rice produced properly by traditional solid-state fermentation using
Monascus fungi is considered to be safe for food use; not only because of its long history
within the Asian diet but also because red yeast rice manufacturers have made every effort
to ensure its safety using various tests, including mutagenicity, acute toxicity, and chronic
toxicity tests. The processed food containing red yeast rice used in a previous clinical trial
has been commercially used for more than 20 years in Japan, and no problematic cases
have been reported from a safety point of view. Furthermore, since red yeast rice pigments
industrially produced with Monascus fungi are approved as food additives, their safety is
institutionally secured by various toxicity tests based on legal standards [7].
Of the Monascus fungi, M. pilosus, M. ruber, and M. purpureus are mainly used for food
in Japan, Taiwan, and China, respectively. It has been reported that the gene encoding
citrinin, a mycotoxin causing renal toxicity, is functional in some strains of M. purpureus
and M. ruber [81,82]. We recently conducted whole-genome analysis of these three strains
of Monascus fungi using a next generation sequencer and demonstrated that M. pilosus
was unable to generate citrinin [83]. This finding indicates that, of the three commercially
used Monascus fungi, only M. pilosus does not generate the mycotoxin, citrinin. Conse-
quently, based on its long history and the results of recent studies, red yeast rice is a safe
material as long as its prepared and used properly.
Figure 18. Expected effect on the circulatory system of red yeast rice and its components.
4. Safety of Red Yeast Rice
Red yeast rice produced properly by traditional solid-state fermentation using Monascus
fungi is considered to be safe for food use; not only because of its long history within the
Asian diet but also because red yeast rice manufacturers have made every effort to ensure
its safety using various tests, including mutagenicity, acute toxicity, and chronic toxicity
tests. The processed food containing red yeast rice used in a previous clinical trial has
been commercially used for more than 20 years in Japan, and no problematic cases have
been reported from a safety point of view. Furthermore, since red yeast rice pigments
industrially produced with Monascus fungi are approved as food additives, their safety is
institutionally secured by various toxicity tests based on legal standards [7].
Of the Monascus fungi, M. pilosus,M. ruber, and M. purpureus are mainly used for food
in Japan, Taiwan, and China, respectively. It has been reported that the gene encoding
citrinin, a mycotoxin causing renal toxicity, is functional in some strains of M. purpureus
and M. ruber [
81
,
82
]. We recently conducted whole-genome analysis of these three strains
of Monascus fungi using a next generation sequencer and demonstrated that M. pilosus was
unable to generate citrinin [
83
]. This finding indicates that, of the three commercially used
Monascus fungi, only M. pilosus does not generate the mycotoxin, citrinin. Consequently,

Molecules 2021,26, 1619 16 of 20
based on its long history and the results of recent studies, red yeast rice is a safe material as
long as its prepared and used properly.
5. Conclusions
In paragraph 1, we introduced that red yeast rice has been a prized medicinal food
in East Asia for about 1500 years, and has been widely used as a food and pigment in
recent years. In paragraph 2, we introduced the metabolites of red yeast rice, mainly
polyketide compounds. These ingredients vary depending on the type of Monascus and
the culture/manufacturing method, but even today, red yeast rice produced by tradi-tional
solid fermentation is widely used as a health food material and we showed the changes in
the amounts of the typical components during the solid-state fermentation process. In the
future, it is expected to develop red yeast rice materials that has more beneficial balances
of ingredients in the safe ancient manufacturing method.
In Section 3, we introduced mainly introduced the findings on the usefulness of red
yeast rice on lipid metabolism and circulatory system. The data from our animal studies
described in Sections 3.1 and 3.2 suggest that in addition to monacolin K, other compo-nents
of red yeast rice may improve lipid metabolism. However, it is a future issue to conduct
experiments with more appropriate controls to clarify in more detail whether the effects
other than LDL-cholesterol lowering effect are due to the red yeast rice component alone or
the combination of monacolin K and red yeast rice components. In addition, the findings of
the effects of statins, pigments, and GABA on the circulatory system as typical components
were introduced in Section 3.3, but the involvement of various components reported to
contain in red yeast rice, such as sterols, decalin compounds, the derivatives, flavonoids,
lignans, coumarins, terpenoids, polysaccha-rides and phenolic acids is unknown [
23
].
Further elucidations of the relationship be-tween each of components of red yeast rice
are expected.
Here, we introduced the typical lipid metabolism and effects of monacolin K (lovas-
tatin) on the lipid metabolism and circulatory system, but recent reports have shown that
monacolin K is also useful for the treatment of neurological disorders, cancer, etc. and
these studies are also being highlighted [
84
]. Furthermore, various functionalities such as
anti-cancer effect, neuroprotective effect, liver protective effect, osteoporosis improving
effect, anti-diabetic effect, anti-obesity effect, anti-fatigue ef-fect, and anti-inflammatory
effect have been reported for red yeast rice [
23
]. It has been suggested that various compo-
nents other than monacolin K are involved in these actions in a complex manner. In the
future, it is expected that evidence will be accumulated and will help improve the quality
of life in a wide range beyond the prevention of lifestyle-related diseases.
In conclusion, red yeast rice is promising as a functional food material that can
maintain and improve health in addition to preventing lifestyle related diseases. As a food
material, it has high medicinal properties, various functions and safety. It is expected that
new values will be elucidated in the future.
Author Contributions:
Conceptualization, H.F.; investigation and resources, Y.H., T.H. (Tomohiro
Hisano) and K.A.; data curation, Y.H., T.H. (Tomohiro Hisano) and K.A.; writing—original draft
preparation, H.F.; writing—review and editing, S.N., T.H. (Tetsuya Hirata), Y.H. and H.F.; visualiza-
tion, H.F. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments:
We thank Yongsu Kim, Kensuke Tachiki., Makoto Tamesada, Takuya Makino,
and Yuki Ozeki for their assistance in experiments, discussions, and literature information. We are
grateful to Tazuru Kikkawa of Kamakura Techno-Science, Inc., for performing the pharmacokinetic
analysis; Tsutomu Tajikawa from the Department of Mechanical Engineering, Faculty of Engineering
Science, Kansai University, for implementation of plasma viscosity experiments; and Skylight Biotech

Molecules 2021,26, 1619 17 of 20
Inc., for analysis of lipoproteins. The authors report no conflicts of interest in the preparation of this
paper. This research received no specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
Conflicts of Interest:
The authors declare no conflict of interest. No funding body had a role in the
writing of this review.
Sample Availability: Samples of the compounds are not available from the authors.
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