Induction of rat liver drug-metabolizing enzymes by heterocycle-containing mono-, di-, tri- and tetra-arylmethanes.
The effect of a nitrogen heterocycle constituent on the ability of arylmethanes to induce phase I and phase II drug-metabolizing enzymes has been examined. Rats were treated with tetra-, tri-, di- or monoarylmethane compounds daily for 3 days at a dose of 75 mg/kg. Induction of UDP-glucuronosyltransferase (morphine) activity was seen with twelve of the eighteen compounds investigated, and for three compounds it occurred independent of any induction of cytochrome P450. Induction of glutathione S-transferase activity was seen with ten of the compounds and was generally paralleled by changes in overall cytochrome P450 concentration and in both pentoxyresorufin and erythromycin dealkylase activities. Major induction of ethoxyresorufin deethylase activity was only apparent with two diarylmethanes that contained a 1-substituted imidazole moiety. UDP-glucuronosyltransferase (1-naphthol) activity was coinduced by these two compounds. A third compound, diphenyl-4-pyridylmethane, induced UDP-glucuronosyltransferase (1-naphthol) activity without increasing ethoxyresorufin deethylase activity. Cytosolic sulfotransferase activity was not induced by the administration of any compound 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 heterocycle, or if the nitrogen atom of the heterocycle was sterically hindered, major induction of cytochrome P450 did not occur. With triarylmethanes, induction was independent of whether the heterocycle was imidazole, pyridine or pyrimidine.
Franklin
M R
MR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008697:Methane / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D006571:Heterocyclic Compounds; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase; D008697:Methane