Translational activation of ethanol-inducible cytochrome P450 (CYP2E1) by isoniazid

The molecular mechanism of ethanol-inducible cytochrome P450(CYP2E1) induction by isoniazid was studied and compared to that of pyridine, an inducer of CYP2E1. Aniline hydroxylase and immunoreactive CYP2E1 protein were significantly induced by isoniazid without or with only slight activation of other cytochromes P450. In contrast, pyridine increased the activities of a broad range of P450s. The effects of two structural analogs of isoniazid, isonicotinamide and isonicotinic acid were also tested and found to have a markedly decreased ability to induce CYP2E1. The induction of CYP2E1 by isoniazid was not accompanied by an increased level of CYP2E1 mRNA, and was completely blocked by pretreatment with cycloheximide or sodium fluoride, inhibitors of mRNA translation. These data thus suggest that CYP2E1 induction by isoniazid is due to activation of CYP2E1 mRNA translation and that the hydrazide group on the pyridine ring of isoniazid is important both in the selective induction of CYP2E1 and for magnitude of effect.