Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-Transferase, and epoxide hydrolase enzymes: Relevance to xenobiotic metabolism and toxicity

In this review, an overview is presented of the current knowledge of geneti c polymorphisms of four of the most important enzyme families involved in t he metabolism of xenobiotics, that is, the N-acetyltransferase (NAT), cytoc hrome P450 (P450), glutathione-S-transferase (GST), and microsomal epoxide hydrolase (mEH) enzymes. The emphasis is on two main topics, the molecular genetics of the polymorphisms and the consequences for xenobiotic metabolis m and toxicity. Studies are described in which wild-type and mutant alleles of biotransformation enzymes have been expressed in heterologous systems t o study the molecular genetics and the metabolism and pharmacological or to xicological effects of xenobiotics. Furthermore, studies are described that have investigated the effects of genetic polymorphisms of biotransformatio n enzymes on the metabolism of drugs in humans and on the metabolism of gen otoxic compounds in vivo as well. The effects of the polymorphisms are high ly dependent on the enzyme systems involved and the compounds being metabol ized. Several polymorphisms are described that also clearly influence the m etabolism and effects of drugs and toxic compounds, in vivo in humans. Futu re perspectives in studies on genetic polymorphisms of biotransformation en zymes are also discussed. It is concluded that genetic polymorphisms of bio transformation enzymes are in a number of cases a major factor involved in the interindividual variability in xenobiotic metabolism and toxicity. This may lead to interindividual variability in efficacy of drugs and disease s usceptibility.