Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility.

Abstract

Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYPlAl, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase Ml (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYPIA 1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations

Involvement of Cytochrome P450, Glutathione S-Transferase, and Epoxide Hydrolase in the Metabolism of Aflatoxin B 1 and Relevance to Risk of Human Liver Cancer

“…With experimental cal carcinogens has been recognized for animal systems, there is considerable evihalf a century (1). Studies on these dence that alterations in levels of some of enzymes have shown their multiplicity in these enzymes can have dramatic effects in many cases, as well as the large extent of influencing the incidence of cancer from (12)(13)(14)(15). Part of the difficulty in this situation may be a result of the myriad of potential carcinogens found in tobacco smoke and the lack of P450 2D6 to dominate in the activation of any of these (16)(17)(18).…”

Genetics in Ankylosing Spondylitis – Beyond HLA-B*27

“…At least 15 allelic variants of CYP2D6, that is inherited as an autosomal recessive trait, can cause poor metaboliser phenotype, but 75% of these are CYP2D6*4 (Brown, et al, 2000). The CYP2D6 genotype was found to be associated with other chronic inflammatory disease and with cancer (Baer, et al, 1986;Daly, et al, 1994).…”

Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease

“…70 Several reviews and meta-analysis were performed to determine whether there is an association between cytochrome P450 polymorphisms (CYP2D6, CYP1A1, CYP2C9, CYP2C19, CYP1A2, and CYP2E1) and the risk of PD. [71][72][73][74][75][76] The most studied is the CYP2D6 gene, which encodes for the enzyme debrisoquine 4-hydroxylase that metabolizes a wide range of drugs, including MPTP, and has a number of functional polymorphisms.…”