Early events in the induction of rat hepatic UDP-glucuronosyltransferases, glutathione S-transferase, and microsomal epoxide hydrolase by 1,7-phenanthroline: comparison with oltipraz, tert-butyl-4-hydroxyanisole, and tert-butylhydroquinone.
Several classes of compounds are able to induce a spectrum of drug-metabolizing enzymes without inducing cytochrome P450s. Examples include antioxidants such as tert-butyl-4-hydroxyanisole and its metabolite tert-butylhydroquinone, dithiolthiones such as oltipraz, and N-heterocycles such as 1,7-phenanthroline. The events associated with induction of UDP-glucuronosyltransferases (UGT), glutathione S-transferases, and microsomal epoxide hydrolase after a single oral dose of these agents have been compared. No agent significantly elevated any of these enzyme activities within 24 h, but oltipraz and 1,7-phenanthroline significantly increased glutathione S-transferase and UGT activities by 48 h. 1, 7-Phenanthroline and oltipraz showed generally similar time-course responses of drug-metabolizing enzyme mRNAs; little change from control at 6 h followed by significant and maximal increases 12 to 18 h after treatment. Maximal mRNA changes for 1,7-phenanthroline and oltipraz were of similar magnitude and clustered around 4-fold for most enzymes. With the exception of one UGT isozyme (UGT1A1), the elevations in mRNA were blocked by prior administration of actinomycin D, indicative of a transcription-dependent response. Neither tert-butyl-4-hydroxyanisole nor tert-butylhydroquinone caused a statistically significant increase in any mRNA examined at any time point.
Lamb
J G
JG
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112-5820, USA.
Franklin
M R
MR
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004798:Enzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010618:Phenanthrolines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors
D004798:Enzymes; D006873:Hydroquinones; D007527:Isoenzymes; D010618:Phenanthrolines; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C053486:1,7-phenanthroline; D002083:Butylated Hydroxyanisole; C026209:oltipraz; C018855:2-tert-butylhydroquinone; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases