Molecular basis for differences in susceptibility to toxicants: introduction

Many toxicants depend upon metabolism for their elimination and/or conversion to the toxic species. As a consequence, differences in metabolism can have a profound influence on interspecies and interindividual susceptibility to toxicity. Until relatively recently, the molecular basis for such differences were not known. However, over the past decade and a half, our understanding of the factors controlling the expression and regulation of the enzymes of drug metabolism has increased dramatically. Thus, the molecular basis of the common polymorphisms of drug metabolism in man, in CYP2D6 (debrisoquine 4-hydroxylase) and NAT2 (arylamine N-acetyltransferase) has been determined, and considerable progress has been made in elucidating the regulatory control of inducible enzymes such as CYP1A1 and CYP4A1. The number of drug metabolising enzymes subject to genetic polymorphism in man is not known, but rare genetic differences in enzymes such as epoxide hydrolase are increasingly being implicated in susceptibility to toxicants previously attributed to idiosyncrasy Indeed, the whole concept of idiosyncrasy in reactions to toxicants is being rendered obsolete by such advances. As information on the basis of differences in susceptibility accrues, the challenge is to apply this knowledge in identifying the "at risk" population. Although much progress has been made in this area, there are still many unanswered questions. What controls the tissue, and indeed cell, selective expression of some enzymes of drug metabolism? What is the molecular basis of species differences in specificity? And most importantly, what factors beyond metabolism are involved in determining susceptibility, and how do these interact with differences in metabolism?