Genetic influences on drug abuse are recognized, but their mechanisms are ill-defined. The metabolism of abused drugs plays an important role in their toxicity, and recent studies have found that differences occur among individuals in the metabolism of a number of drugs. This polymorphic metabolism arises from genetic differences in the expression of drug-metabolizing enzymes, and can have profound effects on drug action. While the metabolism of alcohol and several model drugs is under polymorphic control, essentially nothing is known about the role of polymorphism in the metabolism of commonly abused drugs. Polymorphic metabolism is a possible explanation for individual variations observed in sensitivity to abused drugs; it is also a likely one, as two enzyme systems known to be under polymorphic control (serum cholinesterase and cytochrome P-450) are active in the metabolism of abused drugs such as cocaine, amphetamine, and fentanyl. The relevance of polymorphic metabolism to differences in drug effect depends upon the specificity of an isozyme (i.e. single gene product of a family of related enzymes) for the drug, the pharmacokinetic and pharmacodynamic significance of the pathway, and the extent of the polymorphism within populations. We propose to test the hypothesis that genetic polymorphism does effect the metabolism of drugs of abuse by investigating 1) the selectivity of cytochrome P-450 isozymes for the oxidative metabolism of cocaine, amphetamine, and fentanyl, and 2) the selectivity of serum and tissue esterase isozymes for the hydrolytic metabolism of cocaine. Selectivity will be determined by the induction and inhibition of specific isozymes, screening for strain selectivity, and purification fo enzymes. From these studies, model system will be developed to study increased or decreased metabolism of the drugs by specific enzymes. 3) These model systems will then be used to test the effect of enzyme variants on the pharmacokinetics, and selected biochemical and pharmacodynamic endpoints of the drugs. 4) Biochemical characterization of the relevant enzymes will then allow for the development of screening assays to detect polymorphic metabolism of drugs of abuse. Data from these studies will contribute to the elucidation of mechanisms for individual sensitivity to drugs of abuse, and provide methods to determine the extent of polymorphism within populations.
