The influence of inducers on drug-metabolizing enzyme activity and on formation of reactive drug metabolites in the liver.

A variety of environmental agents can affect the rate of drug biotransformation in the liver by induction of drug-metabolizing enzymes. Both phase I and phase II reactions (the first and second stages of drug metabolism) may be influenced, and epoxide hydrolase, glucuronosyl transferases and glutathione-S-transferases are examples of enzymes which, in addition to the cytochrome P-450-linked monooxygenase system, are readily inducible by environmental agents. Phenobarbitone and 3-methylcholanthrene are the most widely studied representatives of two major classes of inducers. Induction of hepatic drug-metabolizing enzymes is often associated with enhanced detoxification of drugs and other foreign chemicals that are metabolized by these enzymes. However, during recent years, the effect of induction on many compounds has been found to be the opposite, i.e. toxicity is increased. This is true for most hepatotoxic drugs and major groups of chemical carcinogens; experiments with carbon tetrachloride, bromobenzene and benzo[alpha]pyrene serve to illustrate this point in the present paper. It is concluded that the toxicological significance of induction of drug-metabolising enzymes may differ from one substrate to another, and that general conclusions about the beneficial or harmful effects of induction should not be drawn.