Induction of drug metabolizing enzymes by 1,7-phenanthroline and oltipraz in mice is unrelated to Ah-responsiveness.
The protective effect of several classes of compounds against the toxic and neoplastic effects of xenobiotics has been attributed to the induction of noncytochrome P450 (P450) drug metabolizing enzymes. Glutathione S-transferases (GST), NAD(P)H: quinone oxidoreductase (QOR), and UDP-glucuronosyltransferases (UGT) play a prominent role in detoxification and can be induced by oltipraz and other N-heterocyclic compounds in rats. In contrast to the induction of these enzymes by aryl hydrocarbon (Ah)-receptor agonists, induction by oltipraz and 1,7-phenanthroline is not accompanied by CYP1A induction. This study investigated the induction of drug metabolizing enzymes following administration of oltipraz and 1,7-phenanthroline in four mouse strains (C57B6A-J, Frings x C57B6J, Frings, CF-1) exhibiting varying degrees of responsiveness to an Ah-receptor agonist. The relative Ah responsiveness was determined in all strains by the induction of hepatic Cypla after three daily doses of 3-methylcholanthrene (20 mg/kg). After treatment with 1,7-phenanthroline and oltipraz (150 mg/kg i.g.) daily for 3 days, all strains showed similar induction of GST and QOR activities for each inducer. Both compounds were equally effective in elevating GST activity, but 1,7-phenanthroline was more effective than oltipraz in elevating QOR activity. In addition to GST and QOR changes, 1,7-phenanthroline significantly elevated UGT (1-naphthol) activity in the Frings strain. Neither compound produced significant changes in Cypla parameters. The independence of 1,7-phenanthroline and oltipraz induction of GST and QOR from Cypla-responsiveness is in line with the concept that N-heterocycle-containing inducers act by mechanisms other than an Ah-receptor-dependent pathway in which the P450 response has been masked or prevented.
Carr
B A
BA
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Franklin
M R
MR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D005982:Glutathione Transferase / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D010618:Phenanthrolines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D013045:Species Specificity; D013871:Thiones; D013876:Thiophenes
D010618:Phenanthrolines; D011719:Pyrazines; D018336:Receptors, Aryl Hydrocarbon; D013871:Thiones; D013876:Thiophenes; C053486:1,7-phenanthroline; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase