Induction of plasma and tissue enzymes by drugs: significance in toxicological studies

Abstract

1. Observations of drug metabolism enzyme induction in animals during early toxicological trials, and phase I or II of clinical trials, are of importance for the development of a new chemical of pharmacological interest. 2. Induction can be detected by determination of enzyme activities or enzyme proteins in tissues (subcellular fractions or cells in culture). 3. Indirect methods for checking induction can involve determinations of endogenous (i.e. glucaric acid, 6-beta-hydroxycortisol) or xenobiotic (antipyrine) metabolites which are produced by the inducible enzyme systems. 4. Recent progress in the knowledge of biochemical mechanisms of induction and the large number of identified isoenzymes in each enzyme 'family' have complicated the interpretation in pharmaco-toxicological studies. 5. This paper describes the present state of the art concerning the relationships between the isoenzymes and the major classes of inducers concerning cytochromes P-450, UDP-glucuronosyltransferases, gamma-glutamyltransferase and epoxide hydrolases.