METABOLIC POLYMORPHISMS

Polymorphisms have been detected in a variety of xenobiotic-metabolizi ng 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 muta tions which give rise to a defective phenotype have now been identifie d. Another group of enzymes show definite polymorphism at the phenotyp ic level but the exact genetic mechanisms responsible are not yet clea r. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP 2C form which metabolizes mephenytoin, a flavin-linked monooxygenase ( fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilber t's syndrome) and thiopurine S-methyltransferase. In the case of a fur ther group of enzymes, there is some evidence for polymorphism at eith er the phenotypic or genotypic level but this has not been unambiguous ly demonstrated. Examples of this class include the cytochrome P450 en zymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidas e which metabolizes carbocysteine, epoxide hydrolase, two forms of sul photransferase 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 metabol ism and susceptibility to chemically-induced diseases.