Cytochrome P450, family 1, member A1

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

Function
CYP1A1 is involved in phase I is_associated_with::xenobiotic and is_associated_with::drug metabolism (one substrate of it is is_associated_with::theophylline). It is inhibited by is_associated_with::fluoroquinolones and is_associated_with::macrolides and induced by is_associated_with::aromatic hydrocarbons.

CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons (is_associated_with::polycyclic aromatic hydrocarbons, PAH), for example, is_associated_with::benzo(a)pyrene (BP), by transforming it to an is_associated_with::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 is_associated_with::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 is_associated_with::carcinogen.

However, an in vivo experiment with gene-deficient mice has found that the hydroxylation of is_associated_with::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.

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 is_associated_with::aryl hydrocarbon receptor, a ligand activated is_associated_with::transcription factor, and the is_associated_with::aryl hydrocarbon receptor nuclear translocator. In the intestine, but not the liver, CYP1A1 expression moreover depends on TOLL-like receptor 2 (is_associated_with::TLR2), which recognizes bacterial surface structures such as is_associated_with::lipoteichoic acid.

Polymorphisms
Several polymorphisms have been identified in CYP1A1, some of which lead to more highly inducible AHH activity. CYP1A1 polymorphisms include:
 * M1, T→C substitution at is_associated_with::nucleotide 3801 in the 3'-non-coding region
 * M2, A→G substitution at nucleotide 2455 leading to an amino acid change of is_associated_with::isoleucine to is_associated_with::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 is_associated_with::threonine to is_associated_with::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.