Cytochrome P450, family 1, member A1

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

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, benzopyrene (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.^[4]

Regulation

The expression of the CYP1A1 and CYP1B1 genes are regulated by the aryl hydrocarbon receptor, a ligand activated transcription factor.^[5]

Polymorphisms

Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:^[6][7][8][9]

• 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

Further reading