Interpatient variability: genetic predisposition and other genetic factors

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known. This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes. Selected are the polymorphic enzymes of cytochromes P-450 (CYP) as examples of phase I enzymes and methyl transferases, n-acetyl transferases, and glutathione-s-transferases as examples of phase II enzymes. The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described. Phase I enzymatic reactions are predominantly oxidative, whereas phase II reactions often couple with the byproducts of phase I. Overall, in poor metabolizers, whether phase I or phase II, there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists. Drug metabolism also depends on whether the parent compound is a prodrug that forms an active metabolite, and poor metabolizers under this condition will form only trace amounts of an active compound. Therefore, the clinical significance of genetic polymorphisms and other genetic factors may be related to substrate, metabolite, or the major elimination pathway.