Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors

Abstract

1. In the safety evaluation of drugs and other chemicals it is important to evaluate their possible inducing and inhibitory effects on the enzymes of drug metabolism.

2. While many similarities exist between species in their response to inducers and inhibitors, there are also important differences. Possible mechanisms of such variation are considered, with particular reference to the cytochrome P-450 system.

3. Differences in inhibition may be due to differences in inhibitory site of the enzyme involved, which is not always the active site of the enzyme, in competing pathways or in the pharmacokinetics of the inhibitor.

4. Differences in induction could be due to differences in the nature of the induction mechanism, in the isoenzyme induced, in tissue-or age-dependent regulation, in competing pathways for the substrate or its products, or in the pharmacokinetics of the inducing agent.

5. Examples of each of these possible differences are considered, often from our own work on the P450 IA subfamily, and results in animals are compared with those in humans, where possible.

6. At present, the differences between species in their response to inducers and inhibitors make extrapolation to humans from the results of animal studies difficult, so that ultimately such effects should be studied in the species of interest, humans.