{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''Cytochrome P450 4F8''' is a protein that in humans is encoded by the ''CYP4F8'' gene.<ref name="Bylund_1999">{{cite journal | vauthors = Bylund J, Finnström N, Oliw EH | title = Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 1 | pages = 169–174 | date = July 1999 | pmid = 10405341 | doi = 10.1006/bbrc.1999.1011 | bibcode = 1999BBRC..261..169B }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CYP4F8 cytochrome P450, family 4, subfamily F, polypeptide 8 | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=11283 }}</ref>
== Gene ==
This gene, CYP4F8, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, ''CYP4F3'', is located approximately 18 kb away.<ref name="entrez" />
== Tissue distribution == In addition to seminal vesicles, ''CYP4F8'' is expressed in the kidney, prostate, epidermis, and corneal epithelium, and its mRNA has been detected in the retina. ''CYP4F8'' is also greatly up-regulated in psoriatic skin.<ref>{{cite journal | vauthors = Stark K, Wongsud B, Burman R, Oliw EH | title = Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8 | journal = Archives of Biochemistry and Biophysics | volume = 441 | issue = 2 | pages = 174–181 | date = Sep 2005 | pmid = 16112640 | doi = 10.1016/j.abb.2005.07.003 }}</ref>
== Function ==
The CYP4F8 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. These activities are particularly relevant in the seminal vesicles, where these metabolic pathways may influence local prostaglandin signaling.
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,<ref name="Johnson_2015">{{cite book | vauthors = Johnson AL, Edson KZ, Totah RA, Rettie AE | chapter = Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer | title = Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer | volume = 74 | pages = 223–262 | date = 2015 | pmid = 26233909 | pmc = 4667791 | doi = 10.1016/bs.apha.2015.05.002 | series = Advances in Pharmacology | isbn = 978-0-12-803119-3 }}</ref> 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.<ref name="Westphal_2011">{{cite journal | vauthors = Westphal C, Konkel A, Schunck WH | title = CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? | journal = Prostaglandins & Other Lipid Mediators | volume = 96 | issue = 1–4 | pages = 99–108 | date = November 2011 | pmid = 21945326 | doi = 10.1016/j.prostaglandins.2011.09.001 | doi-access = free }}</ref> The enzyme metabolizes DHA primarily to 19''R'',20''S''-epoxyeicosapentaenoic acid and 19''S'',20''R''-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and EPA primarily to 17''R'',18''S''-eicosatetraenoic acid and 17''S'',18''R''-eicosatetraenoic acid isomers (termed 17,18-EEQ).<ref name="Westphal_2011" /> 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.<ref name="Fleming_2014">{{cite journal | vauthors = Fleming I | title = The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease | journal = Pharmacological Reviews | volume = 66 | issue = 4 | pages = 1106–1140 | date = October 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 | s2cid = 39465144 }}</ref><ref>{{cite journal | vauthors = Zhang G, Kodani S, Hammock BD | title = Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer | journal = Progress in Lipid Research | volume = 53 | pages = 108–123 | date = January 2014 | pmid = 24345640 | pmc = 3914417 | doi = 10.1016/j.plipres.2013.11.003 }}</ref><ref>{{cite journal | vauthors = He J, Wang C, Zhu Y, Ai D | title = Soluble epoxide hydrolase: A potential target for metabolic diseases | journal = Journal of Diabetes | volume = 8 | issue = 3 | pages = 305–313 | date = December 2015 | pmid = 26621325 | doi = 10.1111/1753-0407.12358 | doi-access = free }}</ref><ref name="Wagner_2014">{{cite journal | vauthors = Wagner K, Vito S, Inceoglu B, Hammock BD | title = The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling | journal = Prostaglandins & Other Lipid Mediators | volume = 113-115 | pages = 2–12 | date = October 2014 | pmid = 25240260 | pmc = 4254344 | doi = 10.1016/j.prostaglandins.2014.09.001 }}</ref> 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.<ref name="Fleming_2014" /><ref name="Wagner_2014" /><ref>{{cite journal | vauthors = 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 | title = Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway | journal = Journal of Lipid Research | volume = 55 | issue = 6 | pages = 1150–1164 | date = March 2014 | pmid = 24634501 | pmc = 4031946 | doi = 10.1194/jlr.M047357 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Hardwick JP | title = Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases | journal = Biochemical Pharmacology | volume = 75 | issue = 12 | pages = 2263–2275 | date = Jun 2008 | pmid = 18433732 | doi = 10.1016/j.bcp.2008.03.004 }}</ref>
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.<ref name="Johnson_2015" />
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Simpson AE | title = The cytochrome P450 4 (CYP4) family | journal = General Pharmacology | volume = 28 | issue = 3 | pages = 351–359 | date = March 1997 | pmid = 9068972 | doi = 10.1016/S0306-3623(96)00246-7 }} * {{cite journal | vauthors = Bylund J, Hidestrand M, Ingelman-Sundberg M, Oliw EH | title = Identification of CYP4F8 in human seminal vesicles as a prominent 19-hydroxylase of prostaglandin endoperoxides | journal = The Journal of Biological Chemistry | volume = 275 | issue = 29 | pages = 21844–21849 | date = July 2000 | pmid = 10791960 | doi = 10.1074/jbc.M001712200 | doi-access = free }} * {{cite journal | vauthors = Oliw EH, Stark K, Bylund J | title = 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 | journal = Biochemical Pharmacology | volume = 62 | issue = 4 | pages = 407–415 | date = August 2001 | pmid = 11448449 | doi = 10.1016/S0006-2952(01)00683-9 }} * {{cite journal | vauthors = Stark K, Törmä H, Cristea M, Oliw EH | title = Expression of CYP4F8 (prostaglandin H 19-hydroxylase) in human epithelia and prominent induction in epidermis of psoriatic lesions | journal = Archives of Biochemistry and Biophysics | volume = 409 | issue = 1 | pages = 188–196 | date = January 2003 | pmid = 12464258 | doi = 10.1016/S0003-9861(02)00511-8 }} * {{cite journal | vauthors = Stark K, Bylund J, Törmä H, Sahlén G, Oliw EH | title = 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 | journal = Prostaglandins & Other Lipid Mediators | volume = 75 | issue = 1–4 | pages = 47–64 | date = January 2005 | pmid = 15789615 | doi = 10.1016/j.prostaglandins.2004.09.014 }} * {{cite journal | vauthors = Stark K, Wongsud B, Burman R, Oliw EH | title = Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8 | journal = Archives of Biochemistry and Biophysics | volume = 441 | issue = 2 | pages = 174–181 | date = September 2005 | pmid = 16112640 | doi = 10.1016/j.abb.2005.07.003 }} {{refend}}
{{Cytochrome P450}} Category:Cytochrome P450