CYP4F8 explained

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.^{[1] [2]}

Function

This gene, CYP4F8, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and functions as a 19-hydroxylase of the arachidonic acid metabolite, prostaglandin H2 (PGH2) and the Dihomo-γ-linolenic acid metabolite PGH1 in seminal vesicles. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F3, is approximately 18 kb away.^[2] In addition to seminal vesicles, CYP4F8 is expressed in kidney, prostate, epidermis, and corneal epithelium, and its mRNA has been found in retina; CYP4F8 is also greatly up-regulated in psoriatic skin.^[3]

In addition to its ability to metabolize and presumably thereby to inactivate or reduce the activity of PGH2 and PGH1, CYP4F8 adds hydroxyl residues to carbons 18 and 19 of arachidonic acid and Dihomo-γ-linolenic acid,^[4] CYP458 possesses epoxygenase activity in that it metabolizes the omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid, (EPA) to their corresponding epoxides, the epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs), respectively.^[5] The enzyme metabolizes DHA primarily to 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and EPA primarily to 17R,18S-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ).^[5] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule which acts to constrict arterioles, elevate blood pressure, promote inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDPs (see Epoxydocosapentaenoic acid) and EEQs (see epoxyeicosatetraenoic acid) have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.^{[6] [7] [8] [9]} It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, DHA acid and EPA, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.^{[6] [9] [10]} EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally.

CYP4F8 has little activity in omega-hydroxylating leukotriene B4, prostaglandin D2, prostaglandin E2, prostaglandin E1, or prostaglandin F2.^[11]

The fatty acid metabolizing activity, including the ability to form epoxides, of CYP4F8 is very similar to that of CYP4F12. However, it and CYP4F12 are not regarded as being major contributors in forming the cited epoxides in humans although they might do so in tissues where they are highly expressed.^[4]

Further reading

• Simpson AE . The cytochrome P450 4 (CYP4) family . General Pharmacology . 28 . 3 . 351–9 . March 1997 . 9068972 . 10.1016/S0306-3623(96)00246-7 .
• Bylund J, Hidestrand M, Ingelman-Sundberg M, Oliw EH . Identification of CYP4F8 in human seminal vesicles as a prominent 19-hydroxylase of prostaglandin endoperoxides . The Journal of Biological Chemistry . 275 . 29 . 21844–9 . July 2000 . 10791960 . 10.1074/jbc.M001712200 . free .
• Oliw EH, Stark K, Bylund J . Oxidation of prostaglandin H(2) and prostaglandin H(2) analogues by human cytochromes P450: analysis of omega-side chain hydroxy metabolites and four steroisomers of 5-hydroxyprostaglandin I(1) by mass spectrometry . Biochemical Pharmacology . 62 . 4 . 407–15 . August 2001 . 11448449 . 10.1016/S0006-2952(01)00683-9 .
• Stark K, Törmä H, Cristea M, Oliw EH . Expression of CYP4F8 (prostaglandin H 19-hydroxylase) in human epithelia and prominent induction in epidermis of psoriatic lesions . Archives of Biochemistry and Biophysics . 409 . 1 . 188–96 . January 2003 . 12464258 . 10.1016/S0003-9861(02)00511-8 .
• Stark K, Bylund J, Törmä H, Sahlén G, Oliw EH . On the mechanism of biosynthesis of 19-hydroxyprostaglandins of human seminal fluid and expression of cyclooxygenase-2, PGH 19-hydroxylase (CYP4F8) and microsomal PGE synthase-1 in seminal vesicles and vas deferens . Prostaglandins & Other Lipid Mediators . 75 . 1–4 . 47–64 . January 2005 . 15789615 . 10.1016/j.prostaglandins.2004.09.014 .
• Stark K, Wongsud B, Burman R, Oliw EH . Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8 . Archives of Biochemistry and Biophysics . 441 . 2 . 174–81 . September 2005 . 16112640 . 10.1016/j.abb.2005.07.003 .

Notes and References

1. Bylund J, Finnström N, Oliw EH . Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles . Biochemical and Biophysical Research Communications . 261 . 1 . 169–74 . July 1999 . 10405341 . 10.1006/bbrc.1999.1011 .
2. Web site: Entrez Gene: CYP4F8 cytochrome P450, family 4, subfamily F, polypeptide 8.
3. 16112640 . 2005 . Stark . K . Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8 . Archives of Biochemistry and Biophysics . 441 . 2 . 174–81 . Wongsud . B . Burman . R . Oliw . E. H. . 10.1016/j.abb.2005.07.003 .
4. Book: Johnson AL, Edson KZ, Totah RA, Rettie AE . Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer . Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer . 74 . 223–62 . 2015 . 26233909 . 4667791 . 10.1016/bs.apha.2015.05.002 . Advances in Pharmacology . 9780128031193 .
5. Westphal C, Konkel A, Schunck WH . CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? . Prostaglandins & Other Lipid Mediators . 96 . 1–4 . 99–108 . November 2011 . 21945326 . 10.1016/j.prostaglandins.2011.09.001 .
6. Fleming I . The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease . Pharmacological Reviews . 66 . 4 . 1106–40 . October 2014 . 25244930 . 10.1124/pr.113.007781 . 39465144 .
7. Zhang G, Kodani S, Hammock BD . Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer . Progress in Lipid Research . 53 . 108–23 . January 2014 . 24345640 . 3914417 . 10.1016/j.plipres.2013.11.003 .
8. He J, Wang C, Zhu Y, Ai D . Soluble epoxide hydrolase: A potential target for metabolic diseases . Journal of Diabetes . 8 . 3 . 305–13 . December 2015 . 26621325 . 10.1111/1753-0407.12358 . free .
9. Wagner K, Vito S, Inceoglu B, Hammock BD . The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling . Prostaglandins & Other Lipid Mediators . 113-115 . 2–12 . October 2014 . 25240260 . 4254344 . 10.1016/j.prostaglandins.2014.09.001 .
10. Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH . Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway . Journal of Lipid Research . 55 . 6 . 1150–1164 . March 2014 . 24634501 . 4031946 . 10.1194/jlr.M047357 . free .
11. 18433732 . 2008 . Hardwick . J. P. . Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases . Biochemical Pharmacology . 75 . 12 . 2263–75 . 10.1016/j.bcp.2008.03.004 .