Polymorphic Variants of Cytochrome P450: Relevance to Cancer and Other Diseases.

Associations of cytochrome P450 (CYP) polymorphisms with risk of disease development have been reported widely. For lung cancer, a large number of studies on CYP1A1, CYP2D6, and CYP2A6 polymorphisms have been performed. However, recent studies, including meta-analyses and genome-wide association studies, suggest that only the CYP2A6 association, where genotypes associated with low activity decrease susceptibility possibly due to slower nicotine metabolism, appears significant. Associations with lung cancer susceptibility have also been reported for CYP1A2, CYP1B1, and CYP2E1 polymorphisms but these, though biologically plausible, have not been well replicated. For cancers where exposure to xenobiotics other than tobacco smoke affects risk, CYP polymorphisms may also be relevant. Examples include CYP3A for hepatocellular carcinoma due to aflatoxin exposure, CYP1A2 for colon cancer associated with heterocyclic arylamine exposure and CYP2E1 for nitrosamine-related nasopharyngeal cancer. For other diseases, a well-established example relates to CYP1B1 where homozygosity for rare mutations occurs in primary congenital glaucoma. Rare CYP1B1 mutations and possibly polymorphisms may also contribute to risk for more common forms of glaucoma. CYP2C isoforms and CYP2J2 contribute to extrahepatic metabolism of arachidonic acid to epoxyeicosanoic acids which have effects in the cardiovascular system. Genotype for these isoforms may be relevant to risk of cardiovascular disease but evidence is still lacking. CYP2C19 poor metabolizers may be at increased risk of endometriosis, and CYP2E1 genotype may modulate risk of development of alcoholic liver disease. In conclusion, CYP polymorphisms are relevant to risk for some diseases but this may have been overstated in earlier studies.