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J Kermanshah Univ Med Sci. 2022 June; 26(2):e120412.
Published online 2022 September 4.
doi: 10.5812/jkums-120412.
Research Article
The Interfering Effect of Lanthanum on Intestinal Iron Uptake Using
Everted Gut Sac (EGS) Method
Sara Torabi 1, Ali Asghar Moshtaghie1, *, Ali Asghar Rastegari 1and Kahin Shahanipour 1
1Department of Biochemistry, Falavarjan Branch, Islamic Azad University, Falavarjan, Iran
*Corresponding author: Department of Biochemistr y, Falavarjan Branch, Islamic Azad University, Falavarjan, Iran. Email: imancell2010@gmail.com
Received 2021 October 16; Revised 2022 August 17; Accepted 2022 August 17.
Abstract
Background: A dysregulated iron metabolism can lead to a wide range of diseases, and investigating this issue is vital for the de-
velopment of therapeutics. Furthermore, trace elements such as lanthanum have been shown to interfere with iron uptake.
Objectives: Therefore, this study aimed to evaluate the intestinal uptake of lanthanum and its competition with iron uptake.
Methods: This study was conducted using the everted gut sac method on freshly-prepared rat everted gut sacs, which were incu-
bated in Earle’s medium, including iron and lanthanum. The effects of ascorbic acid, glucose, and time intervals were investigated
on lanthanum and iron intestinal uptake. In addition, the interfering effect of lanthanum on iron uptake was scrutinized.
Results: The absorption of iron and lanthanum is saturated at 200 mg/L concentration. Using ascorbic acid (as a reducing agent)
and glucose (as an energy source) increase the absorption of these elements (P < 0.05), and lanthanum reduces iron uptake by up
to 19.3%. The results revealed that the highest uptake occurs in 30 minutes in which, the average uptakes for iron and lanthanum
was 36.6 and 17.6 µg, respectively.
Conclusions: According to the results, lanthanum reduces iron uptake because of competing with iron. Lanthanum could also
interfere with iron metabolism and cause iron-related metabolic disorders. Further studies at the molecular and intracellular levels
are required to understand this mechanism.
Keywords: Iron, Lanthanum, Everted Gut Sac, Absorption, Interference
1. Background
The essential element iron plays a vital role in cell
proliferation, metabolism, and growth (growth-limiting
factor) in almost all organisms (1). Iron is essential for
oxygen-carrying, DNA synthesis, enzyme and redox catal-
ysis, energy production, and cellular respiration (2). Iron
metabolism dysregulation can cause a wide range of dis-
eases, and understanding its role is vital in therapeutics
search (3).
Since humans have no active mechanism for excret-
ing iron, iron absorption by the proximal small intestine
is strictly controlled. The epithelial cells of the upper je-
junum and upper and mid villus in the duodenum are
the first mediators of intestinal iron absorption (4). Di-
etary iron is imported across the brush-border membrane,
stored in ferritin (an intracellular stage), exported across
the basolateral membrane (4,5). Studies have shown that
iron absorption increases in the presence of ascorbic acid
as a reducing agent for changing ferric (III) to ferrous
(II) and glucose as an energy source for transporting iron
throughout the cells (6,7).
Iron uptake has been studied extensively over the past
few decades, but its possible interference with some trace
elements has not received the attention it deserves. Lan-
thanum is a chemical element composed of stable La-139
(99.911%) and (ii) radioactive La-138 (0.089%) isotopes (8).
Various food items and tap water contain trace amounts
of this rare-earth element. This cation of trivalent hard
acid exhibits a high affinity for phosphate and pH inde-
pendence (9). The use of lanthanum in medicine has been
proven in several studies, which can be used as a safe inor-
ganic phosphate binder in patients on dialysis (10). Ascor-
bic acid enhances iron absorption the most among organic
acids because of its chelating and reducing properties (11).
Glucose, in particular, affects iron bioavailability and can
chelate mineral iron, forming low molecular weight solu-
ble complexes, which increases iron absorption (12).
2. Objectives
The study of iron metabolism, especially its absorption
process, is essential due to its vital role in the human body.
The effect of trace elements on iron absorption is an area of
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Torabi S et al.
great interest, but the effect of lanthanum on iron absorp-
tion has not yet been studied. Hence, this study aimed to
evaluate the intestinal uptake of lanthanum and its com-
petition with iron uptake.
3. Methods
The everted gut sac (EGS) method was used to evalu-
ate the intestinal uptake of iron and lanthanum. In these
studies, the method is useful for examining the in-vitro ab-
sorption mechanisms of drugs, the roles of transporters
in drug absorption, intestinal metabolism of drugs, and
the role of intestinal enzymes in the transport of drugs
through the intestine (13). The materials were provided
by Sigma Chemical Company U.K. Male Wistar rats were
obtained from Falavarjan Islamic Azad University (Isfa-
han, Iran) and were kept in standard condition until they
reached 200 - 250 g. In the EGS model, rats were fasted one
day before the experiment and anesthetized with ether.
Then, the duodenum, ileum, or jejunum of their intestine
was rapidly removed and divided into 5 - 6 cm segments.
Each segment was washed with a physiological solution
(pH 6.5, 4°C). The glassware used in the experiment was
soaked overnight in nitric acid 10%. Then, the washed in-
testine was gently everted over a glass rod. One end of the
everted intestine was clamped and tied with a braided silk
suture and filled with 2 mL krebs-ringer bicarbonate (KRB)
solution at 37°C. Then, the other end of the segment was
tied with a thread. EGS segments were ready to be exam-
ined for the effect of various factors (13). A study of iron ab-
sorption in the form of ferric was conducted to investigate
iron absorption.
The EGS segments were first placed in separate test
tubes containing 5 mL of krebs-ringer bicarbonate buffer
(pH 7.4) to determine the optimal concentration for the in-
testinal absorption of iron and lanthanum by EGS. Then,
a mixture of oxygen-carbon dioxide (95: 5) and various
concentrations of iron and lanthanum were complexed
with citrate (0 - 200 mg/L). Then, iron (III) chloride, and
lanthanum (III) chloride were prepared in bi-distilled wa-
ter and mixed with equal volumes of citric acid 1:20. The
contents of the EGS segments were removed after 60 min
of incubation at 37°C. The concentrations of iron and lan-
thanum were measured using uv2600 Spectrophotometry
(Shimadzu, Japan). By using inductively coupled plasma
(ICP) technology, 100 µL of EGS segments’ content were di-
luted with 100 µL of nitric acid 0.2% and the lanthanum
concentration was determined at 240 nm wavelength (13).
A total of 2 mL of Earls buffer (pH 7.4) was added to
the EGS segments, which were inserted into the test tube
containing 5 mL of the Earls’s buffer and different concen-
trations of iron and lanthanum. Besides these substances,
glucose (5 mM) and ascorbic acid (2.8 mM) were tested for
their effects on lanthanum and iron uptake at different
concentrations (0 - 200 mg/L). The concentration of iron
and lanthanum in the EGS segments was investigated after
incubation at 37°C in line with the previous methods (14).
The same steps (mentioned above) were followed to in-
vestigate the interfering effect of lanthanum on intestinal
iron absorption. 2 mL of Earls buffer (pH 7.4) was added
into the EGS segments. These segments were inserted into
the test tube containing 5 mL of Earls’s buffer. In this two-
stage test, the iron intestinal absorption process was inves-
tigated (0 - 200 mg/L) in the presence (100 mg/L) and ab-
sence of lanthanum for its different concentrations. In the
next stage, the iron intestinal absorption process for dif-
ferent concentrations of lanthanum (0 - 200 mg/L) was in-
vestigated in the presence (100 mg/L) and absence of iron.
Iron and lanthanum concentrations were measured after
60 minutes of incubation (37°C) (14).
The elements’ uptake was examined at different time
intervals (15 minutes) to investigate the effect of time on
intestinal uptake. The EGS segments were removed from
the medium, and the iron and lanthanum concentrations
were measured at different time intervals, which was 100
mg/L in each experiment (14).
The data were expressed in mean ±standard error
and analyzed by two-way ANOVA using GraphPad Prism 9
(GraphPad Software, Inc., La Jolla, CA, USA). A statistically
significant difference between groups is indicated by P <
0.05.
4. Results
Since citrate is an iron chelator, iron was complexed
with citrate to examine iron absorption. Therefore, each
piece was filled with 2 mL of Earls’s buffer and the ends
of the intestine segments were closed with surgical su-
tures after preparing the EGS segments. Then, the EGS
segments were placed in separate mediums containing
iron citrate with different concentrations. Mediums were
then exposed to oxygen at 37°C for 30 min for iron absorp-
tion, and the amount of iron absorbed from the incuba-
tion medium was measured. Similar experiments were
performed with different concentrations of lanthanum.
Figure 1 demonstrates that intestinal absorption of these
elements increases as the concentration of iron and lan-
thanum in the medium increases. The results showed that
the maximum intestinal absorption is 200 mg/L for iron
and lanthanum.
Figure 2 shows the effects of ascorbic acid and glu-
cose on iron and lanthanum uptake, which increases in-
testinal absorption of iron and lanthanum in the incuba-
tion medium at 200 mg/L concentration. The intestinal
iron absorption at 200 mg/L increases by 29.0% in the pres-
ence of ascorbic acid compared to its absence, and the lan-
thanum uptake at the highest concentration in the pres-
ence of ascorbic acid also increase by 8.3%. Both iron and
2 J Kermanshah Univ Med Sci. 2022; 26(2):e120412.
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Torabi S et al.
20
15
10
5
0
60
50
40
30
20
10
0
A B
0 50 100 150 200 0 50 100 150 200
La (+3) mg/L Fe (+3) mg/L
μg La Uptake/gr intestine
μg Fe Uptake/gr intestine
Figure 1. Determining the optimal concentration of intestinal absorption of lanthanum by the EGS. A, iron intestinal uptake; B, lanthanum intestinal uptake. Each point is
the average of three independent experiments in mean ±standard deviation. Lanthanum complexed with citrate (1:20) at 37°C for 60 minutes, and the EGS segments average
weight was 1 gr.
lanthanum absorption increased in the presence of glu-
cose by 2.9% and 25.7%, respectively.
Figure 3 illustrates the effect of constant and variable
concentrations of lanthanum on intestinal iron uptake.
According to the results, lanthanum interferes with iron
intestinal uptake andiron uptake in the EGS segments. The
intestinal uptake of iron reduces by 19.7% in the maximum
concentration of iron in the presence of constant concerta-
tion of lanthanum. Figure 3B presents that iron absorption
decreases gradually as lanthanum concentration increases
(54.6% reduction in the highest lanthanum concentration
compared to the absence of lanthanum).
The effect of time intervals on iron and lanthanum in-
testinal absorption are shown in Figure 4. The results re-
veal that the highest uptake occurs in 30 minutes in which,
the average uptakes for iron and lanthanum are 36.6 and
17.6 µg, respectively.
5. Discussion
The intestinal uptake of lanthanum and iron by the EGS
and their interaction were initially investigated. First, the
optimal intestinal absorption of lanthanum and iron con-
centrations was investigated in the incubation medium.
The iron and lanthanum uptake was investigated at dif-
ferent concentrations by the EGS The results showed the
concentration of lanthanum and iron in the incubation
medium increases by raising its absorption.
Iron deficiency is usually related to low Fe intake, poor
iron absorption, blood loss, diseases, gastrointestinal para-
sites, or increased physiological demands as in pregnancy
(15). The intestinal absorption of trace elements such as
copper, zinc, and nickel. is carried out through an active
transfer mechanism (16,17). Previous studies have shown
that iron transfer from intestinal mucosal cells is energy-
dependent, which is absorbed through an active transfer
mechanism, and the energy required for its absorption is
provided by cellular metabolism (18). The present study
examined iron and lanthanum uptake mechanisms to an-
swer examine the energy dependence of their transport
through intestinal mucosal cells and their absorption by
the EGS in the presence of glucose? The results showed
that, iron and lanthanum absorption and the possibility
of the active transfer of iron and lanthanum increases in
the presence of glucose in the incubation medium. This
result is consistent with that of previous studies showing
that glucose increases iron absorption in the gut (12).
Although iron can be absorbed in ferrous (II) and fer-
ric (III) forms in intestinal mucosal cells, the absorption of
ferrous form is high, and ascorbic acid was used to reduce
iron (III) (7,19). Ascorbic acid significantly increases iron
absorption and the intestinal absorption of lanthanum,
but it is not significant. The results revealed that reducing
these elements causes an increase in intestinal absorption.
Studies have shown that, various proteins are involved
in the transport and storage of iron in these cells in intesti-
nal mucosal cells. These proteins include transferrin and
ferritin, which play a controlling role in the absorption of
iron in mucosal cells (20,21). The transferrin in intestinal
mucosal cells causes this protein may also play a role in the
J Kermanshah Univ Med Sci. 2022; 26(2):e120412. 3
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Torabi S et al.
60
50
40
30
20
10
0
24
20
16
12
8
4
0
20
16
12
8
4
0
Ascorbic acid absence
Ascorbic acid present
Iron
Iron + glucose
Lanthanum
Lanthanum + glucose
Ascorbic acid absence
Ascorbic acid present
μg Fe Uptake/gr intestineμg Fe Uptake/gr intestine
μg La Uptake/gr intestineμg La Uptake/gr intestine
0 50 100 150 200
0 50 100 150 200 0 50 100 150 200
0 50 100 150 200
Fe (+3) mg/L
Fe (+3) mg/L
La (+3) mg/L
La (+3) mg/L
70
60
50
40
30
20
10
0
A B
C D
Figure 2. The comparison of iron and lanthanum intestinal uptake in the presence and absence of ascorbic acid and glucose. The ascorbic acid and glucose concentrations
added to the EGS external medium are 2.8 mM and 5 mM, respectively.Each point is the average of three independent experiments in mean ±standard deviation. Lanthanum
complexed with citrate (1: 20) at 37°C for 60 minutes, and the EGS segments average weight was 1 g. Each point represents the group mean (mean ±standard error of the
mean) (*: P < 0.05, **: P < 0.01).
intestinal absorption of lanthanum. This study results also
found that iron absorption reduces slightly in the presence
of lanthanum.
As shown in Figure 3, the lanthanum interfering ef-
fect was studied by EGS in the intestinal absorption of
iron. At high concentrations of lanthanum, iron absorp-
tion gradually decreases, confirming lanthanum’s inter-
fering effect on iron absorption. In addition to the role
transferrin likely plays in the intestinal absorption of lan-
thanum, which is well known, the transferrin molecule has
also been linked to intestinal iron absorption (22). There-
fore, lanthanum is probably absorbed by intestinal mu-
cosal cells with the same mechanism as iron. Due to trans-
ferrin’s role in intestinal iron absorption, these two ele-
ments can compete at the absorption site and interfere
with each other’s metabolism. In previous reports, the in-
terference effect of trivalent cations has been proven in the
binding of iron to apotransferrin, which is consistent with
our results (23).
The effect of incubation time was also investigated on
4 J Kermanshah Univ Med Sci. 2022; 26(2):e120412.
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Torabi S et al.
μg Fe Uptake/gr intestine
μg Fe Uptake/gr intestine
40
30
20
10
0
80
60
40
20
0
0 50 100 150 200 0 50 100 150 200
La (+3) mg/LFe (+3) mg/L
Lanthanum absence
Lanthanum presence
AB
Figure 3. A, The presence and absence of lanthanum on intestinal uptake of iron; and B, the different concentration effect of lanthanum on intestinal uptake of iron. The
constant concentration of iron used in the (B) chart is 100 mg/L. Each point is the average of three independent experiments in mean ±standard deviation. Lanthanum
complexed with citrate (1: 20) at 37°C for 60 minutes, and the EGS segments average weight was 1 g. Each point presents the group mean (mean ±standard error of the mean
(*: P < 0.05, **: P < 0.01).
60
50
40
30
20
10
0
20
15
10
5
0
AB
μg Fe Uptake/gr intestine
μg La Uptake/gr intestine
Time (min) Time (min)
0 15 30 45 60 75 0 15 30 45 60 75
Figure 4. The effect of time on the intestinal absorption of A, iron; and B, lanthanum. The EGS segments were removed from medium, and the concentrations of iron and
lanthanum were measured at different intervals. The iron and lanthanum concentration was 100 mg/L in each experiment. Each point is the average of three independent
experiments in mean ±standard deviation. The lanthanum complexed with citrate (1: 20) at 37°C, for 60 minutes, and the EGS segments average weight was 1 g.
the adsorption of these two elements. Using the EGS to
measure intestinal absorption of iron and lanthanum, it
was found that the maximum absorption occurred around
30 minutes, and then the absorption decreased. The de-
creased absorption may be due to the loss of intestinal mu-
cosal cell life. However, all physiological conditions have
been considered in carrying out this project. Previous stud-
ies have also shown that iron uptake by the intestine occurs
5 - 30 minutes after incubation, which agrees with the find-
ings of this study (24,25).
J Kermanshah Univ Med Sci. 2022; 26(2):e120412. 5
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Torabi S et al.
5.1. Conclusions
The results of this study revealed that lanthanum
could affect the first step of intestinal iron absorption.
However, more investigation is needed at the molecular
and intracellular levels to better understand lanthanum
interference with iron uptake and its metabolism.
Acknowledgments
This study was supported by the grant of Islamic Azad
University of Falavarjan (172481287606911162282609). The
authors thank the Atomic Lab and Falavarjan Islamic Azad
University staff.
Footnotes
Authors’ Contribution: Ali Asghar Moshtaghie and Sara
Torabi developed the original idea and the protocol, ab-
stracted and analyzed data, wrote the manuscript, and
is a guarantor. Ali Asghar Rastegari and Kahin Shaha-
nipour contributed to the development of the protocol, ab-
stracted data, and prepared the manuscript.
Conflict of Interests: The authors declared no conflict of
interest.
Ethical Approval: The university ethics committee ap-
proved all animal protocols with the following ethics code:
IR.IAU.NAJAFABAD.REC.1399.023.
Funding/Support: This study was supported by
the grant of Islamic Azad University of Falavarjan
(172481287606911162282609).
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