Induction of drug metabolism: species differences and toxicological relevance

Abstract

A large number of drugs and other chemicals have been shown to induce hepatic microsomal cytochrome P450 (CYP) forms in experimental animals and humans. Most CYP forms are induced by receptor-mediated mechanisms leading to an increase in gene transcription. Important nuclear receptors involved in the induction of CYP1A, CYP2B, CYP3A and CYP4A subfamily forms comprise, respectively, the aryl hydrocarbon receptor, the constitutive androstane receptor, the pregnane X receptor and the peroxisome proliferator-activated receptor alpha. Hepatic CYP form induction can be assessed by in vivo, ex vivo and in vitro methods. Significant species differences can exist in the enzyme induction response to a given chemical and also in the toxicological consequences of induction. Hepatic CYP form induction in humans may lead to clinically important drug-drug interactions. In rodents hepatic CYP form induction can be associated with the formation of tumours by non-genotoxic modes of action in the liver, thyroid and other tissues.