CYP4A11

Family

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases, catalyzing many reactions involved in drug metabolism as well as the synthesis of cholesterol, steroids, and other lipids.

Tissue and subcellular distribution

CYP4A11 is highly expressed in the liver and kidney. Its primary subcellular localization is in the endoplasmic reticulum, where it participates in the hydroxylation of medium-chain fatty acids such as laurate and myristate.

Function

CYP4A11 plays a crucial role in metabolizing arachidonic acid into 20-Hydroxyeicosatetraenoic acid (20-HETE) via an Omega oxidation reaction. In humans, the predominant enzymes synthesizing 20-HETE are CYP4F2 and CYP4A11. 20-HETE regulates blood flow, vascularization, blood pressure, and renal ion absorption, particularly in rodents and potentially in humans.

In addition to its role in omega oxidation, CYP4A11 exhibits epoxygenase activity, converting docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs). Notably, CYP4A11 does not convert arachidonic acid to epoxides, a function primarily performed by CYP2C and CYP2J subfamily members. EDPs and EEQs generally oppose the effects of 20-HETE, demonstrating potent actions in lowering blood pressure, inhibiting thrombosis and inflammation, and reducing cancer cell growth.

Omega-3-rich diets significantly elevate serum and tissue levels of EDPs and EEQs in both animals and humans, making these metabolites the most prominent polyunsaturated fatty acid derivatives resulting from such diets. name="Wagner K 2014" /

Members of the CYP4A and CYP4F subfamilies, along with CYP2U1, also ω-hydroxylate various fatty acid metabolites of arachidonic acid—including LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins—thereby modulating inflammatory, vascular, and other biological responses.

Clinical significance

Polymorphisms in CYP4A11 are associated with susceptibility to hypertension and cerebral infarction (ischemic stroke) in humans. The T8590C single nucleotide polymorphism (SNP), rs1126742, results in a CYP4A11 variant with significantly reduced enzymatic activity, likely due to a loss-of-function mutation. This variant may reduce the production of EEQs and EDPs, contributing to blood pressure dysregulation. Dietary sesamin, a major lignan in sesame, inhibits CYP4A11, reducing 20-HETE synthesis and lowering its plasma and urinary levels. This inhibition has been demonstrated in both in vitro and human studies. Furthermore, hydroxylation-induced inactivation by CYP4A and CYP4F enzymes is implicated in modulating inflammation, potentially explaining the links between CYP4F2 and CYP4F3 variants and human Crohn's disease and Coeliac disease.

References

References

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6. (Aug 2008). "Association of a CYP4A11 variant and blood pressure in black men". Journal of the American Society of Nephrology.
7. (Mar 2008). "A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men". Journal of Hypertension.
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10. (Mar 2010). "Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population". Pharmacogenetics and Genomics.
11. (Nov 2009). "Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: In vitro and human studies". Hypertension.
12. (Nov 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators.
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14. (Jan 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research.
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