Induction of drug-metabolizing enzymes by xenobiotics

Abstract

1. Isozymes of the cytochromes P-450, UDP-glucuronosyl transferases (UDPGT) and glutathione S-transferases appear to be differentially inducible by prototype inducers, such as 3-methylcholanthrene (MC), phenobarbital, pregnenolone 16 alpha-carbonitrile and clofibrate. 2. Mechanisms of induction include both transcriptional and post-transcriptional control. MC-type inducers (representing a large number of planar polycyclic aromatics, beta-naphthoflavone and polyhalogenated aromatics) bind with high affinity to the Ah receptor which controls gene expression similar to steroid hormone receptors. The Ah receptor controls the expression of several drug metabolizing enzymes. For example, both cytochrome P450 IA1 and UDPGT-1 appear to be co-induced by inducers with widely differing potencies, such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin, 1,2,3,7,8-pentachloro-dibenzo-p-dioxin and benz(a)anthracene. Much less is known about the mechanism of action of other inducer prototypes. 3. Induction and co-induction of drug-metabolizing enzymes are generally considered as adaptive responses leading to more efficient elimination and detoxication of xenobiotics such as benzo(a)pyrene. For example, when the mutagenicity of benzo(a)pyrene and benzo(a)pyrene-3,6-quinone was studied in the Ames test, glucuronidation or glutathione conjugation (concomitant with cytochrome P-450-dependent reactions) markedly decreased their mutagenicity. The protective effect was more pronounced with the homogenate S9 fraction of MC-treated rats. However, at 'non-physiological' levels of exposure enzyme induction may lead to increased toxic risk.