Table 1 - uploaded by Nick Chacos
Content may be subject to copyright.
Source publication
Arachidonic acid is oxidized by a NADPH-dependent oxygenase of rat liver microsomes to a number of oxygen-containing products, which can be resolved by HPLC. Several of these products have been purified and characterized. They exhibit an absorbance in the UV region of the spectrum that has a maximum at approximately 235 nm, indicative of the presen...
Context in source publication
Context 1
... ad- dition, the isomeric composition of the HETEs formed by this enzymatic reaction system is dramatically different from that observed following autooxidation of monodisperse or micellar arachidonic acid or superoxide-dependent metal-catalyzed cooxidation of micellar arachidonic acid (7,8,19). The rates of Biochemistry: Capdevila et aL formation of the individual HETEs (Table 1) imply that oxida- tion occurs preferentially toward the methyl terminus. How- ever, we cannot rule out the possibility that 5-and 8-HETEs are produced but are selectively further metabolized to prod- ucts that do not absorb at 235 nm. ...
Similar publications
As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that...
Citations
... One of the AA-metabolites of this subclass is 11-HETE, which can be biosynthesized either by COX-1/2, CYP, or non-enzymatically as byproduct of AA auto-oxidation [127,128]. Mainly due to this auto-oxidative biosynthesis, 11-HETE is described as a marker for lipid peroxidation, a process known to occur in MS and thought to be related to inflammation, demyelination and neurodegeneration [129,130]. However, no receptors for 11-HETE have been identified to date and 11-HETE itself has never been linked to MS before. ...
Background
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive.
Main body
This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS.
Short conclusion
The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS.
Graphical Abstract
... It is metabolized by cyclooxygenase and lipoxygenase (LOX) enzymes to form prostaglandins and leukotrienes, respectively. In the 1980s, it was discovered that cytochrome P450 (CYP) enzymes also metabolize AA into bioactive eicosanoids (Capdevila et al. 1982). ...
Hydroxyeicosatetraenoic acids (HETEs) are hydroxylated arachidonic acid (AA) metabolites that are classified into midchain, subterminal, and terminal HETEs. Hydroxylation results in the formation of R and S enantiomers for each HETE, except for 20-HETE. HETEs have multiple physiological and pathological effects. Several studies have demonstrated sex-specific differences in AA metabolism in different organs. In this study, microsomes from the heart, liver, kidney, lung, intestine, and brain of adult male and female Sprague–Dawley rats were isolated and incubated with AA. Thereafter, the enantiomers of all HETEs were analyzed by liquid chromatography-tandem mass spectrometry. We found significant sex- and enantiospecific differences in the formation levels of different HETEs in all organs. The majority of HETEs, especially midchain HETEs and 20-HETE, showed significantly higher formation rates in male organs. In the liver, the R enantiomer of several HETEs showed a higher formation rate than the corresponding S enantiomer (e.g., 8-, 9-, and 16-HETE). On the other hand, the brain and small intestine demonstrated a higher abundance of the S enantiomer. 19(S)-HETE was more abundant than 19(R)-HETE in all organs except the kidney. Elucidating sex-specific differences in HETE levels provides interesting insights into their physiological and pathophysiological roles and their possible implications for different diseases.
... Cytochrome P450 enzymes such as epoxygenase and mixed hyprolase metabolize AA to produce various lipid mediators. The CYP epoxygenase enzyme is responsible for the production of AA epoxides or epoxyeicosatrienoic acids (EETs;14,11,8,and 5,, whereas -hydroxylase is responsible for the production of hydroxyeicosatetraenoic acids (HETEs) (Capdevila et al., 1982;Wang et al., 2021). ...
... Cytochrome P450 enzymes such as epoxygenase and mixed hyprolase metabolize AA to produce various lipid mediators. The CYP epoxygenase enzyme is responsible for the production of AA epoxides or epoxyeicosatrienoic acids (EETs;14,11,8,and 5,, whereas -hydroxylase is responsible for the production of hydroxyeicosatetraenoic acids (HETEs) (Capdevila et al., 1982;Wang et al., 2021). ...
Inflammation and resolution are highly programmed processes involving a plethora of immune cells. Lipid mediators synthesized from arachidonic acid metabolism play a pivotal role in orchestrating the signaling cascades in the game of inflammation. The majority of the studies carried out so far on inflammation were aimed at inhibiting the generation of inflammatory molecules, whereas recent research has shifted more towards understanding the resolution of inflammation. Owing to chronic inflammation as evident in neuropathophysiology, the resolution of inflammation together with the class of lipid mediators actively involved in its regulation has attracted the attention of the scientific community as therapeutic targets. Both omega-three polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, orchestrate a vital regulatory role in inflammation development. Resolvins derived from these fatty acids comprise the D-and E-series resolvins. A growing body of evidence using in vitro and in vivo models has revealed the pro-resolving and anti-inflammatory potential of resolvins. This systematic review sheds light on the synthesis, specialized receptors, and resolution of inflammation mediated by resolvins in Alzheimer's and Parkinson's disease.
... The cytochrome P450 pathway, which is considered as the third eicosanoid pathway, was first described in 1980 [8]. The CYP450 pathway produces four regioisomers of epoxyeicosatrienoic acids, 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET, which are hydrolyzed by the sEH to DHETs with very low biological activity [3]. ...
... The two metabolic pathways not only process a large spectrum of physiological and pathophysiological effects, but also have been transformed as therapeutic targets for a variety of diseases, for example the clinical application of prostaglandins, aspirin, and leukotriene receptor antagonists [22]. The CYP450 pathway was firstly described as the third AA metabolizing pathway in 1980 [8]. The CYP450 family of enzymes contains many subclasses of which the ωhydroxylase and epoxygenase activity are the most important for the metabolism of AA [3]. ...
Inflammation plays a crucial role in the initiation and development of a wide range of systemic illnesses. Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid (AA) metabolized by CYP450 epoxygenase (CYP450) and are subsequently hydrolyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs), which are merely biologically active. EETs possess a wide range of established protective effects on many systems of which anti-inflammatory actions have gained great interest. EETs attenuate vascular inflammation and remodeling by inhibiting activation of endothelial cells and reducing cross-talk between inflammatory cells and blood vessels. EETs also process direct and indirect anti-inflammatory properties in the myocardium and therefore alleviate inflammatory cardiomyopathy and cardiac remodeling. Moreover, emerging studies show the substantial roles of EETs in relieving inflammation under other pathophysiological environments, such as diabetes, sepsis, lung injuries, neurodegenerative disease, hepatic diseases, kidney injury, and arthritis. Furthermore, pharmacological manipulations of the AA-CYP450-EETs-sEH pathway have demonstrated a contribution to the alleviation of numerous inflammatory diseases, which highlight a therapeutic potential of drugs targeting this pathway. This review summarizes the progress of AA-CYP450-EETs-sEH pathway in regulation of inflammation under different pathological conditions and discusses the existing challenges and future direction of this research field.
... The cytochrome P450 (CYP) is the second metabolizing pathway of AA that mainly produces hydroxyeicosatetraenoic acids (HETEs) due to its ω-hydroxylase activity. However, CYP epoxygenase activity resulted in producing epoxyeicosatrienoic acids (EETs) that can further have metabolized by epoxide hydrolase and generate the corresponding diols [5]. Pieces of evidence revealed the vasodilatation effect of EETs as well as their regulatory role on the tumorigenesis process [6]. ...
15-lipoxygenase is one of the key enzymes for the metabolism of unsaturated fatty acids that its manipulation has been proposed recently as a new molecular target for regulating cancer cell growth. Aberrant expression of 15-lipoxygenase enzyme seems to play an indicative role in the pathology of different cancer types, tumor progression, metastasis, or apoptosis. Based on the fact that breast cancer is one of the most common cancers that imposes a burden of mortality in women also, on the other hand, evidence in experimental models and human studies indicate the emerging role of the 15-lipoxygenase pathway in breast cancer pathogenesis, we present a review of recent findings related to the role of 15- lipoxygenase enzyme and metabolites in breast cancer growth, apoptosis, metastasis, and invasion as well as their local and circulating expression pattern in patients with breast cancer. Our review supports the emerging role of 15- lipoxygenase in molecular and cellular processes regulating breast tumor cell fate with both positive and negative effects.
... The third AA metabolizing pathway is the cytochrome P450 (CYP) pathway that was first described in 1980. The CYP family of enzymes contains numerous subclasses, 17 but for the metabolism of AA ω-hydroxylase and epoxygenase activity are the most important. However, numerous CYP enzymes have mixed hyprolase and epoxygenase functions and are able to generate a mixed spectrum of products. ...
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
... A single dose of IR (6 Gy) significantly elevated the levels of malondialdehyde (MDA). The main product of lipid peroxidation and cytotoxic nitric oxide in the liver [74,75]. In our study, we found that IR (4Gy) increased the MDA levels in mice and crocin treatment restores the MDA level ( Table 2). ...
Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.
... A single dose of IR (6 Gy) significantly elevated the levels of malondialdehyde (MDA). The main product of lipid peroxidation and cytotoxic nitric oxide in the liver [74,75]. In our study, we found that IR (4Gy) increased the MDA levels in mice and crocin treatment restores the MDA level ( Table 2). ...
Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.
... [47] The plasma levels of 9-HETE and 11-HETE were also found to be suppressed by nonfermented garlic supplementation. However, the ambiguous biosynthesis of 9-HETE and 11-HETE involves both cytochrome P450 dependent oxygenation [48] and lipid peroxidation. [49] Insofar, the role of 9-and 11-HETE is suggested to involve in generic inflammation, [50] atherosclerosis, [50] ischemia, [51] and myocardial infarction, [52] which are conditions highly related to the risk of disease development in patients with hypercholesterolemia. ...
Dietary garlic has been shown to alleviate hypercholesterolemia, a condition associated to development of cardiovascular disease. Reactive oxygen species takes part in the disease progression, but it is unknown if antioxidant rich garlic arrests lipid and cholesterol oxidation in hypercholesterolemia. In this study we provided fermented garlic or non‐fermented garlic to mild hypercholesterolemia (total cholesterol: 5.2‐6.2 mmol/L) and determined its ability to relief in vivo oxidative stress by measuring multiple oxidized lipid products of polyunsaturated fatty acid (PUFA) and cholesterol oxidation products (COPs) in plasma. Plasma fatty acids levels were also analysed. After 13 weeks supplementation, both groups showed a significant increase in α‐linolenic acid level (p < 0.05). Levels of arachidic acid increased and palmitoleic acid decreased in the group supplemented with non‐fermented garlic. Of the oxidized PUFA products, notably those derived from enzymatic oxidation of arachidonic acid namely hydroxyeicosatetraenoic acid (HETE) showed a significant difference. Levels of lipoxygenase mediated 5‐HETE and 12‐HETE, and CYP‐P450 mediated 9‐HETE and 11‐HETE decreased after non‐fermented garlic supplementation only (p < 0.05). Non‐enzymatic PUFA oxidation and COPs were not altered by garlic supplementation. Overall, only non‐fermented garlic intake showed selective antioxidant properties in mild hypercholesterolemia where limited effect was found in reducing lipid oxidation.
Practical applications: Current research provides a new insight for the use of garlic extract as a nutraceutical to reduce in vivo oxidative stress. The modified enzymatic oxidation of arachidonic acid in mild hypercholesterolemia after non‐fermented garlic extract intake potentially prevented the progression of chronic inflammation that can lead to complicated pathologies such as arthritis, cardiovascular diseases and non‐alcoholic fatty liver disease.
