CYP1A1
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
CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (
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
The EDP (see
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 (
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, codon462
- 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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000140465 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032315 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^
Kawajiri K (1999). "CYP1A1". IARC Scientific Publications (148): 159–72. PMID 10493257.
- ^
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. PMID 15128046.
- ^
Smith G, Stubbins MJ, Harries LW, Wolf CR (Dec 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica. 28 (12): 1129–65. PMID 9890157.
- PMID 30558213.
- ^ a b
Beresford AP (1993). "CYP1A1: friend or foe?". Drug Metabolism Reviews. 25 (4): 503–17. PMID 8313840.
- S2CID 24627183.
- S2CID 7634080.
- S2CID 19395455.
- PMID 21945326.
- PMID 27677308.
- ^ PMID 25244930.
- PMID 24345640.
- PMID 26621325.
- ^ PMID 25240260.
- PMID 24634501.
- ^
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. S2CID 7512239.
- PMID 22442665.
- PMID 25398514.
- PMID 1707592.
- PMID 7901425.
- ^
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. PMID 8001264.
- 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. 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. 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. S2CID 9153325.
