CYP2S1 explained

Cytochrome P450 2S1 is a protein that in humans is encoded by the CYP2S1 gene.^{[1] [2]} The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1.^[3]

Expression

CYP2S1 is highly expressed in epithelial tissues of the respiratory, gastrointestinal, urinary tracts, and skin and in leukocytes of the monocyte/macrophage and lymphocyte series; it is also expressed throughout Embryogenesis and, as discussed below, certain types of cancers.^[3]

Function

This gene 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. In rodents, the homologous protein has been shown to metabolize certain carcinogens although its specific function(s) in humans has not been clearly determined.^[2] In in vitro studies, the human enzyme has been found to metabolize all-trans-retinoic acid to 4-hydroxy-retinoic acid and 5, 6-epoxy-retinoic acid and therefore may play a role in processing retinoic acid in tissues where it is highly expressed such as the skin.^[3] CYP2S1 is significantly overexpressed and, perhaps directly related to this, its gene is significantly hypomethylated (see gene methylation in the skin of Han Chinese patients with psoriasis suggesting that it plays a role in the development of this disease.^[4]

CYP2S1 has been suggested to be involved in the growth and/or spread of certain tumors of epithelial cell origin: its higher expression in breast or colorectal cancer tissues appears associated respectively with shorter survival times or poor prognoses, and it is more highly expressed in metastasis compared to primary tumor tissues of ovarian cancer.^{[3] [5] [6] [7]}

CYP2S1 has recently been assigned epoxygenase activity. It metabolizes 1) arachidonic acid to its various epoxides, i.e., the epoxyeicosatrienoic acids (also termed EETs); 2) docosahexaenoic acid to its various epoxides, i.e. the epoxydocosapentaenoic acids (also termed EDPs); and 3) linoleic acid to its various epoxides, i.e. vernolic acid (also termed leukotoxin) and coronaric acid (also termed isoleukotoxin).^[8] It seems likely, although not yet tested, that CYP231 will also prove able to metabolize other polyunsaturated fatty acids to their epoxides; for example, the enzyme may metabolize eicosapentaenoic acid to epoxyeicosatetraenoic acids (also termed EEQs). Animal model studies implicate the EET, EDP, and EEQ epoxides in regulating blood pressure, tissue blood flow, new blood vessel formation (i.e. angiogenesis, pain perception, and the growth of various cancers; limited studies suggest but have not proven that these epoxides may function similarly in humans (see epoxyeicosatrienoic acid, epoxydocosapentaenoic acid, eicosatetraenoic acid, and epoxygenase pages).^[9] The CYP2S1-dependent production of EETs, which stimulate the growth of various types of cancer cells, including those of the colon (see epoxyeicosatrienoic acid#cancer), could contribute to the unfavorable effects of this CYP in the sited cancers.

Vernolic and coronaric acids are potentially toxic, causing multiple organ failure and acute respiratory distress when injected into animals and suggested to be involved in causing these syndromes in humans.^[9]

CYP2S1 has also been found to metabolize Prostaglandin G2 and Prostaglandin H2 to the biologically active product, 12-Hydroxyheptadecatrienoic acid (i.e. 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, also termed 12-HHT).^[8]

Further reading

• Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence . Nature . 377 . 6547 Suppl . 3–174 . September 1995 . 7566098 . .
• Smith G, Wolf CR, Deeni YY, Dawe RS, Evans AT, Comrie MM, Ferguson J, Ibbotson SH . Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases . Lancet . 361 . 9366 . 1336–43 . April 2003 . 12711469 . 10.1016/S0140-6736(03)13081-4 . 42519228 .
• Saito S, Iida A, Sekine A, Kawauchi S, Higuchi S, Ogawa C, Nakamura Y . Catalog of 680 variations among eight cytochrome p450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population . Journal of Human Genetics . 48 . 5 . 249–70 . 2003 . 12721789 . 10.1007/s10038-003-0021-7 . free .
• Rivera SP, Wang F, Saarikoski ST, Taylor RT, Chapman B, Zhang R, Hankinson O . A novel promoter element containing multiple overlapping xenobiotic and hypoxia response elements mediates induction of cytochrome P4502S1 by both dioxin and hypoxia . The Journal of Biological Chemistry . 282 . 15 . 10881–93 . April 2007 . 17277313 . 10.1074/jbc.M609617200 . free .
• Marek CJ, Tucker SJ, Koruth M, Wallace K, Wright MC . Expression of CYP2S1 in human hepatic stellate cells . FEBS Letters . 581 . 4 . 781–6 . February 2007 . 17280660 . 10.1016/j.febslet.2007.01.056 . 24479485 . 2007FEBSL.581..781M .
• Hanzawa Y, Sasaki T, Hiratsuka M, Ishikawa M, Mizugaki M . Three novel single nucleotide polymorphisms (SNPs) of CYP2S1 gene in Japanese individuals . Drug Metabolism and Pharmacokinetics . 22 . 2 . 136–40 . April 2007 . 17495422 . 10.2133/dmpk.22.136 .
• Jang YJ, Cha EY, Kim WY, Park SW, Shon JH, Lee SS, Shin JG . CYP2S1 gene polymorphisms in a Korean population . Therapeutic Drug Monitoring . 29 . 3 . 292–8 . June 2007 . 17529885 . 10.1097/FTD.0b013e318058a4e0 . 27240042 .

Notes and References

1. Rylander T, Neve EP, Ingelman-Sundberg M, Oscarson M . Identification and tissue distribution of the novel human cytochrome P450 2S1 (CYP2S1) . Biochemical and Biophysical Research Communications . 281 . 2 . 529–35 . February 2001 . 11181079 . 10.1006/bbrc.2001.4390 .
2. Web site: Entrez Gene: CYP2S1 cytochrome P450, family 2, subfamily S, polypeptide 1.
3. Saarikoski ST, Rivera SP, Hankinson O, Husgafvel-Pursiainen K . CYP2S1: a short review . Toxicology and Applied Pharmacology . 207 . 2 Suppl . 62–9 . September 2005 . 16054184 . 10.1016/j.taap.2004.12.027 .
4. Zhou F, Wang W, Shen C, Li H, Zuo X, Zheng X, Yue M, Zhang C, Yu L, Chen M, Zhu C, Yin X, Tang M, Li Y, Chen G, Wang Z, Liu S, Zhou Y, Zhang F, Zhang W, Li C, Yang S, Sun L, Zhang X . Epigenome-Wide Association Analysis Identified Nine Skin DNA Methylation Loci for Psoriasis . The Journal of Investigative Dermatology . 136 . 4 . 779–87 . 2016 . 26743604 . 10.1016/j.jid.2015.12.029 . free .
5. Murray GI, Patimalla S, Stewart KN, Miller ID, Heys SD . Profiling the expression of cytochrome P450 in breast cancer . Histopathology . 57 . 2 . 202–11 . August 2010 . 20716162 . 10.1111/j.1365-2559.2010.03606.x . 3481077 .
6. Kumarakulasingham M, Rooney PH, Dundas SR, Telfer C, Melvin WT, Curran S, Murray GI . Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis . Clinical Cancer Research . 11 . 10 . 3758–65 . May 2005 . 15897573 . 10.1158/1078-0432.CCR-04-1848 . 23287346 .
7. Downie D, McFadyen MC, Rooney PH, Cruickshank ME, Parkin DE, Miller ID, Telfer C, Melvin WT, Murray GI . Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers . Clinical Cancer Research . 11 . 20 . 7369–75 . October 2005 . 16243809 . 10.1158/1078-0432.CCR-05-0466 . 37734580 .
8. Frömel T, Kohlstedt K, Popp R, Yin X, Awwad K, Barbosa-Sicard E, Thomas AC, Lieberz R, Mayr M, Fleming I . Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques . Basic Research in Cardiology . 108 . 1 . 319 . January 2013 . 23224081 . 10.1007/s00395-012-0319-8 . 9158244 .
9. Spector AA, Kim HY . Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1851 . 4 . 356–65 . April 2015 . 25093613 . 10.1016/j.bbalip.2014.07.020 . 4314516.