CYP1A1

CYP1A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4I8V
Identifiers
Aliases	CYP1A1, AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX, CYPIA1, cytochrome P450 family 1 subfamily A member 1
External IDs	OMIM: 108330; MGI: 88588; HomoloGene: 68062; GeneCards: CYP1A1; OMA:CYP1A1 - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q24.1 Start 74,719,542 bp[1] End 74,725,536 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 B|9 31.34 cM Start 57,595,211 bp[2] End 57,611,107 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle jejunal mucosa islet of Langerhans trachea right lobe of liver epithelium of colon urinary bladder cartilage tissue skin of leg mucosa of urinary bladder Top expressed in transitional epithelium of urinary bladder lip olfactory epithelium gastrula right lung embryo embryo skin of external ear jejunum skin of abdomen More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding oxygen binding flavonoid 3'-monooxygenase activity demethylase activity oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen metal ion binding steroid hydroxylase activity catalytic activity protein binding heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen enzyme binding vitamin D 24-hydroxylase activity oxidoreductase activity aromatase activity oxidoreductase activity, acting on diphenols and related substances as donors monooxygenase activity estrogen 16-alpha-hydroxylase activity Hsp70 protein binding Hsp90 protein binding Cellular component cytoplasm organelle membrane endoplasmic reticulum membrane intracellular membrane-bounded organelle membrane endoplasmic reticulum mitochondrion mitochondrial inner membrane Biological process response to immobilization stress maternal process involved in parturition response to hypoxia 9-cis-retinoic acid biosynthetic process response to organic cyclic compound coumarin metabolic process vitamin D metabolic process insecticide metabolic process response to hyperoxia response to antibiotic demethylation cellular response to organic cyclic compound response to virus ageing hepatocyte differentiation epoxygenase P450 pathway dibenzo-p-dioxin catabolic process response to arsenic-containing substance response to organic substance positive regulation of G1/S transition of mitotic cell cycle response to vitamin A response to lipopolysaccharide omega-hydroxylase P450 pathway response to wounding dibenzo-p-dioxin metabolic process response to nematode response to iron(III) ion flavonoid metabolic process response to food liver development camera-type eye development digestive tract development cell population proliferation response to herbicide porphyrin-containing compound metabolic process ethylene metabolic process lipid hydroxylation steroid metabolic process cellular response to copper ion amine metabolic process toxin metabolic process response to toxic substance regulation of lipid metabolic process heterocycle metabolic process hydrogen peroxide biosynthetic process developmental process long-chain fatty acid biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1543 13076 Ensembl ENSG00000140465 ENSMUSG00000032315 UniProt P04798 P00184 RefSeq (mRNA) NM_000499 NM_001319216 NM_001319217 NM_001136059 NM_009992 RefSeq (protein) NP_000490 NP_001306145 NP_001306146 NP_001129531 NP_034122 Location (UCSC) Chr 15: 74.72 – 74.73 Mb Chr 9: 57.6 – 57.61 Mb PubMed search [3] [4]
Wikidata
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Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein^[5] that in humans is encoded by the CYP1A1 gene.^[6] The protein is a member of the cytochrome P450 superfamily of enzymes.^[7]

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),^[8] fluoroquinolones and macrolides and induced by aromatic hydrocarbons.^[9]

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.^[9]

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.^[10]

CYP1A1 metabolism of various foreign agents to carcinogens has been implicated in the formation of various types of human cancer.^[11][12]

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-epoxydocosapentaenoic acid and 19S,20R-epoxydocosapentaenoic 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).^[13] Synthesis of 12(S)-HETE by CYP1A1 has also been demonstrated.^[14] 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.^{[15][16][17][18]} 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.^[15][18][19] 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^[18] 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.^[20] In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (TLR2),^[21] 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.^[22]

Polymorphisms

Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:^{[23][24][25][26]}

• M1, T→C substitution at nucleotide 3801 in the 3'-non-coding region
• M2, A→G substitution at nucleotide 2455 leading to an amino acid change of isoleucine to valine at codon 462
• M3, T→C substitution at nucleotide 3205 in the 3'-non-coding region
• M4, C→A substitution at nucleotide 2453 leading to an amino acid change of threonine to asparagine at codon 461

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.

References

1. GRCh38: Ensembl release 89: ENSG00000140465 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032315 – 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. Kawajiri K (1999). "CYP1A1". IARC Scientific Publications (148): 159–72. PMID 10493257.
6. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW (Jan 2004). "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. doi:10.1097/00008571-200401000-00001. PMID 15128046.
7. Smith G, Stubbins MJ, Harries LW, Wolf CR (Dec 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
8. 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. (2018). "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics. 10 (4): 277. doi:10.3390/pharmaceutics10040277. PMC 6321138. PMID 30558213.
9. Beresford AP (1993). "CYP1A1: friend or foe?". Drug Metabolism Reviews. 25 (4): 503–17. doi:10.3109/03602539308993984. PMID 8313840.
10. Uno S, Dalton TP, Derkenne S, Curran CP, Miller ML, Shertzer HG, Nebert DW (May 2004). "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. doi:10.1124/mol.65.5.1225. PMID 15102951. S2CID 24627183.
11. Badal S, Delgoda R (Jul 2014). "Role of the modulation of CYP1A1 expression and activity in chemoprevention". Journal of Applied Toxicology. 34 (7): 743–53. doi:10.1002/jat.2968. PMID 24532440. S2CID 7634080.
12. Go RE, Hwang KA, Choi KC (Mar 2015). "Cytochrome P450 1 family and cancers". The Journal of Steroid Biochemistry and Molecular Biology. 147: 24–30. doi:10.1016/j.jsbmb.2014.11.003. PMID 25448748. S2CID 19395455.
13. Westphal C, Konkel A, Schunck WH (Nov 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.
14. Nguyen, CH; Brenner, S; Huttary, N; Atanasov, AG; Dirsch, VM (September 2016). "AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis". Hum Mol Genet. 27: ddw329. doi:10.1093/hmg/ddw329. PMID 27677308.
15. Fleming I (Oct 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID 25244930.
16. Zhang G, Kodani S, Hammock BD (Jan 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
17. He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. 8 (3): 305–13. doi:10.1111/1753-0407.12358. PMID 26621325.
18. Wagner K, Vito S, Inceoglu B, Hammock BD (Oct 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.
19. 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 (Mar 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.
20. Ma Q, Lu AY (Jul 2007). "CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies". Drug Metabolism and Disposition. 35 (7): 1009–16. doi:10.1124/dmd.107.015826. PMID 17431034. S2CID 7512239.
21. Do KN, Fink LN, Jensen TE, Gautier L, Parlesak A (2012). "TLR2 controls intestinal carcinogen detoxication by CYP1A1". PLOS ONE. 7 (3): e32309. Bibcode:2012PLoSO...732309D. doi:10.1371/journal.pone.0032309. PMC 3307708. PMID 22442665.
22. Wohak, L.E.; Krais, A.M.; Kucab, J.E.; Stertmann, J.; Ovrebo, S.; Phillips, D.H.; Arlt, V.M. (2016). "Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism". Arch Toxicol. 90 (2): 291–304. doi:10.1007/s00204-014-1409-1. PMC 4748000. PMID 25398514.
23. Petersen DD, McKinney CE, Ikeya K, Smith HH, Bale AE, McBride OW, Nebert DW (Apr 1991). "Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP". American Journal of Human Genetics. 48 (4): 720–5. PMC 1682951. PMID 1707592.
24. Cosma G, Crofts F, Taioli E, Toniolo P, Garte S (1993). "Relationship between genotype and function of the human CYP1A1 gene". Journal of Toxicology and Environmental Health. 40 (2–3): 309–16. Bibcode:1993JTEH...40..309C. doi:10.1080/15287399309531796. PMID 7901425.
25. Crofts F, Taioli E, Trachman J, Cosma GN, Currie D, Toniolo P, Garte SJ (Dec 1994). "Functional significance of different human CYP1A1 genotypes". Carcinogenesis. 15 (12): 2961–3. doi:10.1093/carcin/15.12.2961. PMID 8001264.
26. Kiyohara C, Hirohata T, Inutsuka S (Jan 1996). "The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene". Japanese Journal of Cancer Research. 87 (1): 18–24. doi:10.1111/j.1349-7006.1996.tb00194.x. PMC 5920980. PMID 8609043.

Further reading

• Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW (Jan 2004). "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. doi:10.1097/00008571-200401000-00001. PMID 15128046.
• Masson LF, Sharp L, Cotton SC, Little J (May 2005). "Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: a HuGE review". American Journal of Epidemiology. 161 (10): 901–15. doi:10.1093/aje/kwi121. PMID 15870154.
• Hildebrandt AG, Schwarz D, Krusekopf S, Kleeberg U, Roots I (2007). "Recalling P446. P4501A1 (CYP1A1) opting for clinical application". Drug Metabolism Reviews. 39 (2–3): 323–41. doi:10.1080/03602530701498026. PMID 17786624. S2CID 9153325.