Drug-metabolizing enzyme induction by 2,2'-dipyridyl, 1,7-phenanthroline, 7,8-benzoquinoline and oltipraz in mouse.
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.
Carr
B A
BA
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Franklin
M R
MR
D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013045:Species Specificity; D013871:Thiones; D013876:Thiophenes
D010618:Phenanthrolines; D011719:Pyrazines; D011804:Quinolines; D013871:Thiones; D013876:Thiophenes; C053486:1,7-phenanthroline; D015082:2,2'-Dipyridyl; C026209:oltipraz; C117298:7,8-benzoquinoline; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase