INDUCTION OF RAT-LIVER DRUG-METABOLIZING-ENZYMES BY HETEROCYCLE-CONTAINING MONO-ARYLMETHANES, DI-ARYLMETHANES, TRI-ARYLMETHANES AND TETRA-ARYLMETHANES

The effect of a nitrogen heterocycle constituent on the ability of ary lmethanes to induce phase I and phase II drug-metabolizing enzymes has been examined. Rats were treated with tetra-, tri-, di- or monoarylme thane compounds daily for 3 days at a dose of 75 mg/kg. Induction of U DP-glucuronosyltransferase(morphine) activity was seen with twelve of the eighteen compounds investigated, and for three compounds it occurr ed independent of any induction of cytochrome P450. Induction of gluta thione S-transferase activity was seen with ten of the compounds and w as generally paralleled by changes in overall cytochrome P450 concentr ation and in both pentoxyresorufin and erythromycin dealkylase activit ies. Major induction of ethoxyresorufin deethylase activity was only a pparent with two diarylmethanes that contained a 1-substituted imidazo le moiety. UDP-glucuronosyltransferase(1-naphthol) naphthol) activity was coinduced by these two compounds. A third compound, diphenyl-4-pyr idyl-methane, induced UDP-glucuronosyltransferase(1-naphthol) activity without increasing ethoxy-resorufin deethylase activity. Cytosolic su lfotransferase activity was not induced by the administration of any c ompound in this study. Among arylmethane derivatives, the presence of two aryl groups appeared to be a minimum requirement for induction of drug-metabolizing enzymes. If one of the aryl groups was not a heteroc ycle, or if the nitrogen atom of the heterocycle was sterically hinder ed, major induction of cytochrome P450 did not occur. With triarylmeth anes, induction was independent of whether the heterocycle was imidazo le, pyridine or pyrimidine.