Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the [1 ] CYP1A1 gene. The protein is a member of the [2 ] cytochrome P450 superfamily of enzymes. [3 ]
Function [ edit ]
CYP1A1 is involved in phase I
xenobiotic and drug metabolism (one substrate of it is theophylline). It is inhibited by fluoroquinolones and macrolides and induced by aromatic hydrocarbons. [4 ]
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 (BP), by transforming it to an epoxide. In this reaction, the oxidation of benzo[a]pyrene is catalysed by CYP1A1 to form BP-7,8-epoxide, which can be further oxidized by epoxide hydrolase (EH) to form BP-7,8-dihydrodiol. Finally CYP1A1 catalyses this intermediate to form BP-7,8-dihydrodiol-9,10-epoxide, which is the ultimate carcinogen. [5 ]
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 ]
Regulation [ edit ]
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. In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 ( [7 ] TLR2), which recognizes bacterial surface structures such as [8 ] lipoteichoic acid.
Polymorphisms [ edit ]
polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include: [9 ] [10 ] [11 ] [12 ]
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 [ edit ]
^ Kawajiri K (1999). "CYP1A1". (148): 159–72. IARC Scientific Publications PMID 10493257.
^ Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW (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.
^ Smith G, Stubbins MJ, Harries LW, Wolf CR (1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi: 10.1080/004982598238868. PMID 9890157.
^ Beresford AP (1993). "CYP1A1: friend or foe?". Drug Metabolism Reviews 25 (4): 503–17. doi: 10.3109/03602539308993984. PMID 8313840.
^ Beresford, AP (1993). "CYP1A1: friend or foe?". Drug Metab Rev 25 (4): 503–17. doi: 10.3109/03602539308993984. PMID 8313840.
^ Uno, S (2004). "Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation.". Mol Pharmacol 65 (5): 1225–37. doi: 10.1124/mol.65.5.1225. PMID 15102951.
^ Ma Q, Lu AY (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.
^ Do, KN; Fink, LN; Jensen, TE; Gautier, L; Parlesak, A (2012). "TLR2 controls intestinal carcinogen detoxication by CYP1A1.". PLoS ONE 7 (3): e32309. doi: 10.1371/journal.pone.0032309. PMC 3307708. PMID 22442665.
^ Petersen DD, McKinney CE, Ikeya K, Smith HH, Bale AE, McBride OW, Nebert DW (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.
^ 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. doi: 10.1080/15287399309531796. PMID 7901425.
^ Crofts F, Taioli E, Trachman J, Cosma GN, Currie D, Toniolo P, Garte SJ (1994). "Functional significance of different human CYP1A1 genotypes". Carcinogenesis 15 (12): 2961–3. doi: 10.1093/carcin/15.12.2961. PMID 8001264.
^ Kiyohara C, Hirohata T, Inutsuka S (1996). "The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene". Japanese Journal of Cancer Research 87 (1): 18–24. PMID 8609043.
Further reading [ edit ]
Nelson DR, Zeldin DC, Hoffman SM, et al. (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 (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, et al. (2007). "Recalling P446. P4501A1 (CYP1A1) opting for clinical application.". Drug Metabolism Reviews 39 (2-3): 323–41. doi: 10.1080/03602530701498026. PMID 17786624.