Metabolic polymorphisms

Abstract

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.

The effect of relevant genotypes on PAH exposure-related biomarkers

“…It is known at present that many of the genes coding enzymes involved in activation and detoxification of PAHs are polymorphic, which renders humans at variable risk of developing cancer if exposed (Bartsch and Hietanen, 1996;Daly et al, 1993;d'Errico et al, 1996 ). The metabolism of PAHs is mediated in the initial oxidative step by cytochrome P450 gene products, mainly the isoenzyme CYP1A1 ( Daly et al, 1993;Rannug et al, 1995 ). In phase II conjugation reactions, many carcinogens are detoxified by cytosolic glutathione S-transferases (GSTs) (Eaton and Bammler, 1999;Ketterer.…”

“…However, in view of the role of mEH in both toxication and detoxication reactions of PAH epoxides, the relationship between levels of enzyme activity and susceptibility to cancers is likely to be complex (Daly et al, 1993 ).…”

“…1988 ). On the other hand, epoxide hydrolases ( EHs ) convert biologically reactive epoxides to more watersoluble trans -dihydrodiols, which can have either beneficial or harmful effects, depending on subsequent metabolic pathways ( Daly et al, 1993;Hassett et al, 1994).…”

“…1988 ). On the other hand, epoxide hydrolases ( EHs ) convert biologically reactive epoxides to more watersoluble trans -dihydrodiols, which can have either beneficial or harmful effects, depending on subsequent metabolic pathways ( Daly et al, 1993;Hassett et al, 1994 In 1990 a Japanese group found a close correlation between a polymorphic site in the 3 0 noncoding region of CYP1A1 and smoking -related lung cancer ( Kawajiri et al, 1990 ). The striking relationship between mutations in the CYP1A1 gene and cancer have not been found in Caucasians, among whom the frequency of mutations is approximately 10-fold lower compared to Japanese people ( Hirvonen, 1995 ).…”

The role of individual susceptibility in cancer burden related to environmental exposure.

“…Nine human cDNAs have been cloned to date, and they have been classified into two families, UGT1 and UGT2, on the basis of the similarity of their deduced amino acid sequences (74). Evidence for variability in the general population has been obtained, but no genetic polymorphism of the UGT genes has so far been observed (75). The data based on phenotyping analysis of NNK metabolites, NNAL and NNAL glucuronides, in the urine of smokers suggest the presence of polymorphism in UGT (20).…”