Drug-metabolizing enzyme induction by 2,2′-dipyridyl, 1,7-phenanthroline, 7,8-benzoquinoline and oltipraz in mouse

Abstract

1. Changes in the major hepatic drug-metabolizing enzymes by compounds identified as atypical inducers (multienzyme response but devoid of cytochrome P450-inducing ability) in rat were investigated in mouse. Animals were treated with 1,7-phenanthroline, 2,2′-dipyridyl, 7,8-benzoquinoline and oltipraz at 75 and 150 mg/kg daily for 3 days. 2. UDP-glucuronosyltransferase(UGT) activities showed only limited changes, UGT activity towards 4-nitrophenol and 1-naphthol was induced by the 75 mg/kg dose of 2,2′-dipyridyl and UGT activity towards morphine was induced by 150 mg/kg doses of 7,8-benzoquinoline and oltipraz. UGT activity towards oestrone was not induced by any treatment regimen and showed a decrease following treatment with the lower dose of 7,8-benzoquinoline. 3. In contrast with the limited effect on UGT activities, glutathione S-transferase and NAD(P)H:quinone oxidoreductase activities were significantly elevated by most compounds. Glutathione S-transferase activity was significantly elevated by the 150 mg/kg dose of 1,7-phenanthroline (73%), 2,2′-dipyridyl (52%) and oltipraz (75%), and also the lower dose of 1,7-phenanthroline (47%). NAD(P)H:quinone oxidoreductase activity was significantly elevated by the higher dose of all N-heterocycles (155-323%) as well as the lower dose of 1,7-phenanthroline (180%). 4. In contrast with the effect previously seen in rat, 7,8-benzoquinoline significantly elevated mouse cytochrome P450 concentration but not 7-ethoxyresorufin O-dealkylase activity. As in rat, no N-heterocycle-containing compound significantly elevated pentoxyresorufin O-dealkylase activity. 5. Overall, mouse show a more limited response in the range of drug-metabolizing enzymes induced by N-heterocycles compared with rat, but as in rat, cytochrome P450 was largely unaffected.