CYP1A1 explained

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein[1] that in humans is encoded by the CYP1A1 gene.[2] The protein is a member of the cytochrome P450 superfamily of enzymes.[3]

Function

Metabolism of xenobiotics and drugs

CYP1A1 is involved in phase I xenobiotic and drug metabolism (one substrate of it is theophylline). It is inhibited by hesperetin (a flavonoid found in lime, sweet orange),[4] fluoroquinolones and macrolides and induced by aromatic hydrocarbons.[5]

CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (polycyclic aromatic hydrocarbons, PAH), for example, benzo[a]pyrene (BaP), by transforming it to an epoxide. In this reaction, the oxidation of benzo[a]pyrene is catalysed by CYP1A1 to form BaP-7,8-epoxide, which can be further oxidized by epoxide hydrolase (EH) to form BaP-7,8-dihydrodiol. Finally, CYP1A1 catalyses this intermediate to form BaP-7,8-dihydrodiol-9,10-epoxide, which is a carcinogen.[5]

However, an in vivo experiment with gene-deficient mice has found that the hydroxylation of benzo[a]pyrene by CYP1A1 can have an overall protective effect on the DNA, rather than contributing to potentially carcinogenic DNA modifications. This effect is likely due to the fact that CYP1A1 is highly active in the intestinal mucosa, and thus inhibits infiltration of ingested benzo[a]pyrene carcinogen into the systemic circulation.[6]

CYP1A1 metabolism of various foreign agents to carcinogens has been implicated in the formation of various types of human cancer.[7] [8]

Metabolism of endogenous agents

CYP1A1 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. CYP1A1 has monoxygenase activity in that it metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ).[9] Synthesis of 12(S)-HETE by CYP1A1 has also been demonstrated.[10] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes 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.

The EDP (epoxydocosapentaenoic acid) and EEQ (epoxyeicosatetraenoic acid) metabolites 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.[11] [12] [13] [14] 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, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.[11] [14] [15] 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. CYP1A1 is one of the main extra-hepatic cytochrome P450 enzymes; it is not regarded as being a major contributor to forming the cited epoxides[14] but could act locally in certain tissues such as the intestine and in certain cancers to do so.

Regulation

The expression of the CYP1A1 gene, along with that of CYP1A2/1B1 genes, is regulated by a heterodimeric transcription factor that consist of the aryl hydrocarbon receptor, a ligand activated transcription factor, and the aryl hydrocarbon receptor nuclear translocator.[16] In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (TLR2),[17] which recognizes bacterial surface structures such as lipoteichoic acid. Additionally, the tumour suppressor p53 has been shown to impact CYP1A1 expression thereby modulating the metabolic activation of several environmental carcinogens such as PAHs.[18]

Polymorphisms

Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:[19] [20] [21] [22]

The highly inducible forms of CYP1A1 are associated with an increased risk of lung cancer in smokers. (Reference = Kellerman et al., New Eng J Med 1973:289;934-937) Light smokers with the susceptible genotype CYP1A1 have a sevenfold higher risk of developing lung cancer compared to light smokers with the normal genotype.

Further reading

Notes and References

  1. Kawajiri K . CYP1A1 . IARC Scientific Publications . 148 . 159–72 . 1999 . 10493257 .
  2. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW . Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants . Pharmacogenetics . 14 . 1 . 1–18 . Jan 2004 . 15128046 . 10.1097/00008571-200401000-00001 .
  3. Smith G, Stubbins MJ, Harries LW, Wolf CR . Molecular genetics of the human cytochrome P450 monooxygenase superfamily . Xenobiotica . 28 . 12 . 1129–65 . Dec 1998 . 9890157 . 10.1080/004982598238868 .
  4. Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles. 2018. 30558213. Briguglio. M.. Hrelia. S.. Malaguti. M.. Serpe. L.. Canaparo. R.. Dell'Osso. B.. Galentino. R.. De Michele. S.. Dina. C. Z.. Porta. M.. Banfi. G.. Pharmaceutics. 10. 4. 277. 10.3390/pharmaceutics10040277. 6321138. free.
  5. Beresford AP . CYP1A1: friend or foe? . Drug Metabolism Reviews . 25 . 4 . 503–17 . 1993 . 8313840 . 10.3109/03602539308993984 .
  6. Uno S, Dalton TP, Derkenne S, Curran CP, Miller ML, Shertzer HG, Nebert DW . Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation . Molecular Pharmacology . 65 . 5 . 1225–37 . May 2004 . 10.1124/mol.65.5.1225 . 15102951 . 24627183 .
  7. Badal S, Delgoda R . Role of the modulation of CYP1A1 expression and activity in chemoprevention . Journal of Applied Toxicology . 34 . 7 . 743–53 . Jul 2014 . 24532440 . 10.1002/jat.2968 . 7634080 .
  8. Go RE, Hwang KA, Choi KC . 19395455 . Cytochrome P450 1 family and cancers . The Journal of Steroid Biochemistry and Molecular Biology . 147 . 24–30 . Mar 2015 . 25448748 . 10.1016/j.jsbmb.2014.11.003 .
  9. 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 . Nov 2011 . 21945326 . 10.1016/j.prostaglandins.2011.09.001 .
  10. Nguyen . CH . Brenner . S . Huttary . N . Atanasov . AG . Dirsch . VM . AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis . Hum Mol Genet . September 2016 . 27 . ddw329 . 27677308 . 10.1093/hmg/ddw329. free .
  11. 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 . Oct 2014 . 25244930 . 10.1124/pr.113.007781 . free .
  12. Zhang G, Kodani S, Hammock BD . Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer . Progress in Lipid Research . 53 . 108–23 . Jan 2014 . 24345640 . 3914417 . 10.1016/j.plipres.2013.11.003 .
  13. He J, Wang C, Zhu Y, Ai D . Soluble epoxide hydrolase: A potential target for metabolic diseases . Journal of Diabetes . 8 . 3 . 305–13 . Dec 2015 . 26621325 . 10.1111/1753-0407.12358 . free .
  14. 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 . Oct 2014 . 25240260 . 4254344 . 10.1016/j.prostaglandins.2014.09.001 .
  15. 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 . Mar 2014 . 24634501 . 4031946 . 10.1194/jlr.M047357 . free .
  16. Ma Q, Lu AY . 7512239 . CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies . Drug Metabolism and Disposition . 35 . 7 . 1009–16 . Jul 2007 . 17431034 . 10.1124/dmd.107.015826 .
  17. Do KN, Fink LN, Jensen TE, Gautier L, Parlesak A . TLR2 controls intestinal carcinogen detoxication by CYP1A1 . PLOS ONE . 7 . 3 . e32309 . 2012 . 22442665 . 3307708 . 10.1371/journal.pone.0032309 . 2012PLoSO...732309D . free .
  18. Wohak . L.E. . Krais . A.M. . Kucab . J.E. . Stertmann . J. . Ovrebo . S. . Phillips . D.H. . Arlt . V.M. . Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism . Arch Toxicol . 2016 . 90 . 2 . 291–304 . 10.1007/s00204-014-1409-1 . 25398514. 4748000 .
  19. Petersen DD, McKinney CE, Ikeya K, Smith HH, Bale AE, McBride OW, Nebert DW . Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP . American Journal of Human Genetics . 48 . 4 . 720–5 . Apr 1991 . 1707592 . 1682951 .
  20. Cosma G, Crofts F, Taioli E, Toniolo P, Garte S . Relationship between genotype and function of the human CYP1A1 gene . Journal of Toxicology and Environmental Health . 40 . 2–3 . 309–16 . 1993 . 7901425 . 10.1080/15287399309531796 . 1993JTEH...40..309C .
  21. Crofts F, Taioli E, Trachman J, Cosma GN, Currie D, Toniolo P, Garte SJ . Functional significance of different human CYP1A1 genotypes . Carcinogenesis . 15 . 12 . 2961–3 . Dec 1994 . 8001264 . 10.1093/carcin/15.12.2961 .
  22. Kiyohara C, Hirohata T, Inutsuka S . The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene . Japanese Journal of Cancer Research . 87 . 1 . 18–24 . Jan 1996 . 8609043 . 10.1111/j.1349-7006.1996.tb00194.x . 5920980 .

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