CYP4F12

CYP4F12
Identifiers
Aliases	CYP4F12, CYPIVF12, F22329_1, cytochrome P450 family 4 subfamily F member 12
External IDs	OMIM: 611485; MGI: 1927669; HomoloGene: 81872; GeneCards: CYP4F12; OMA:CYP4F12 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.12 Start 15,673,018 bp[1] End 15,697,174 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 B1 Start 33,124,044 bp[2] End 33,136,316 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon mucosa of ileum right lobe of liver duodenum skin of abdomen skin of leg jejunal mucosa rectum gingival epithelium nasal epithelium Top expressed in intestinal villus jejunum left lobe of liver duodenum Paneth cell ileum crypt of lieberkuhn of small intestine adrenal gland visual cortex left colon More reference expression data BioGPS More reference expression data
Gene ontology Molecular function oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen alkane 1-monooxygenase activity aromatase activity oxidoreductase activity leukotriene-B4 20-monooxygenase activity heme binding metal ion binding iron ion binding arachidonic acid epoxygenase activity monooxygenase activity Cellular component endoplasmic reticulum apical plasma membrane cytoplasm organelle membrane integral component of membrane membrane endoplasmic reticulum membrane intracellular membrane-bounded organelle Biological process arachidonic acid metabolic process pressure natriuresis vitamin E metabolic process epoxygenase P450 pathway long-chain fatty acid metabolic process leukotriene B4 catabolic process very long-chain fatty acid metabolic process sodium ion homeostasis renal water homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 66002 64385 Ensembl ENSG00000186204 ENSMUSG00000024292 UniProt Q9HCS2 Q9EP75 RefSeq (mRNA) NM_023944 NM_001204333 NM_001204334 NM_001204335 NM_001204336 NM_022434 NM_001357788 RefSeq (protein) NP_076433 NP_001191262 NP_001191263 NP_001191264 NP_001191265 NP_071879 NP_001344717 Location (UCSC) Chr 19: 15.67 – 15.7 Mb Chr 17: 33.12 – 33.14 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome P450 4F12 is a protein that, in humans, is encoded by the CYP4F12 gene.^[5][6]

Gene family

The CYP4F12 gene encodes a member of the cytochrome P450 superfamily of enzymes. It is located within a cluster of P450 genes on chromosome 19.^[6][7] Cytochrome P450 proteins are monooxygenases that catalyze a wide array of reactions involved in drug metabolism and in the synthesis of cholesterol, steroids, and other lipids.

Expression and localization

CYP4F12 is thought to localize to the endoplasmic reticulum. It is expressed in the liver and throughout the gastrointestinal tract. The enzyme is known to metabolize the antihistamines ebastine and terfenadine, suggesting it may play a role in the metabolism of these and other drugs.^[7][8]

Substrate specificity

When expressed in yeast, CYP4F12 oxidizes arachidonic acid by hydroxylating carbon 18 or 19 to form 18-HETE or 19-HETE, respectively, though the physiological significance of this activity remains unclear. It also metabolizes prostaglandin H2 (PGH2) and PGH1 to their 19-hydroxyl analogs, potentially reducing their biological activity.^[8]

In addition to monooxygenase activity, CYP4F12 also functions as an epoxygenase. It metabolizes docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two omega-3 fatty acids, to produce epoxide derivatives: DHA → 19R,20S- and 19S,20R-epoxydocosapentaenoic acids (19,20-EDP) EPA → 17R,18S- and 17S,18R-epoxyeicosatetraenoic acids (17,18-EEQ).^[9]

Function

19-HETE, one of CYP4F12’s products, inhibits the activity of 20-HETE, a pro-inflammatory and vasoconstrictive signaling molecule. However, the in vivo importance of this inhibition has yet to be confirmed (see 20-Hydroxyeicosatetraenoic acid). EDPs (see Epoxydocosapentaenoic acid) and EEQs (see epoxyeicosatetraenoic acid) exhibit a wide range of biological activities in animal models and in vitro systems:

• Lower blood pressure^[10] and pain perception^[11][12]
• Suppress inflammation^[11]
• Inhibit angiogenesis, endothelial cell migration and proliferation]^[11]
• Inhibit growth and metastasis of breast and prostate cancer cell lines]^[11]

These findings suggest that EDPs and EEQs may contribute to the beneficial effects of dietary omega-3 fatty acids such as DHA and EPA in humans.^{[10][12][13][14]} These metabolites are short-lived and are rapidly inactivated by epoxide hydrolases, particularly soluble epoxide hydrolase, limiting their action to local environments.

Comparison with CYP4F8

CYP4F12 shares similar enzymatic activity with CYP4F8, particularly in fatty acid metabolism and epoxide formation. However, neither enzyme is considered a major contributor to these processes in humans, although they may play important roles in tissues where they are highly expressed.^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000186204 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024292 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Bylund J, Bylund M, Oliw EH (Feb 2001). "cDna cloning and expression of CYP4F12, a novel human cytochrome P450". Biochemical and Biophysical Research Communications. 280 (3): 892–897. doi:10.1006/bbrc.2000.4191. PMID 11162607.
6. "Entrez Gene: CYP4F12 cytochrome P450, family 4, subfamily F, polypeptide 12".
7. Stark K, Wongsud B, Burman R, Oliw EH (September 2005). "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): 174–181. doi:10.1016/j.abb.2005.07.003. PMID 16112640.
8. Johnson AL, Edson KZ, Totah RA, Rettie AE (January 2015). "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Advances in Pharmacology. 74. San Diego, Calif.: 223–262. doi:10.1016/bs.apha.2015.05.002. ISBN 978-0-12-803119-3. PMC 4667791. PMID 26233909.
9. Westphal C, Konkel A, Schunck WH (November 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326.
10. Fleming I (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–1140. doi:10.1124/pr.113.007781. PMID 25244930. S2CID 39465144.
11. Zhang G, Kodani S, Hammock BD (January 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–123. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
12. Wagner K, Vito S, Inceoglu B, Hammock BD (October 2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators. 113–115: 2–12. doi:10.1016/j.prostaglandins.2014.09.001. PMC 4254344. PMID 25240260.
13. Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, et al. (March 2014). "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. doi:10.1194/jlr.M047357. PMC 4031946. PMID 24634501.
14. He J, Wang C, Zhu Y, Ai D (December 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. 8 (3): 305–313. doi:10.1111/1753-0407.12358. PMID 26621325.

External links

• Human CYP4F12 genome location and CYP4F12 gene details page in the UCSC Genome Browser.

Further reading

• Simpson AE (Mar 1997). "The cytochrome P450 4 (CYP4) family". General Pharmacology. 28 (3): 351–359. doi:10.1016/S0306-3623(96)00246-7. PMID 9068972.
• Knight JA, Fronk S, Haymond RE (Jan 1975). "Chemical basis and specificity of chemical screening tests for urinary vanilmandelic acid". Clinical Chemistry. 21 (1): 130–133. doi:10.1093/clinchem/21.1.130. PMID 1116264.
• Hashizume T, Imaoka S, Hiroi T, Terauchi Y, Fujii T, Miyazaki H, et al. (Feb 2001). "cDNA cloning and expression of a novel cytochrome p450 (cyp4f12) from human small intestine". Biochemical and Biophysical Research Communications. 280 (4): 1135–1141. doi:10.1006/bbrc.2000.4238. PMID 11162645.
• Stark K, Wongsud B, Burman R, Oliw EH (Sep 2005). "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): 174–181. doi:10.1016/j.abb.2005.07.003. PMID 16112640.
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, et al. (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Research : an International Journal for Rapid Publication of Reports on Genes and Genomes. 12 (2): 117–126. doi:10.1093/dnares/12.2.117. PMID 16303743.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (Jan 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.