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-metaboli zing enzymes without inducing cytochrome P450s. Examples include antioxidan ts such as tert-butyl-4-hydroxyanisole and its metabolite tert-butylhydroqu inone, dithiolthiones such as oltipraz, and N-heterocycles such as 1,7-phen anthroline. The events associated with induction of UDP-glucuronosyltransfe rases (UGT), glutathione S-transferases, and microsomal epoxide hydrolase a fter a single oral dose of these agents have been compared. No agent signif icantly elevated any of these enzyme activities within 24 h, but oltipraz a nd 1,7-phenanthroline significantly increased glutathione S-transferase and UGT activities by 48 h. 1,7-Phenanthroline and oltipraz showed generally s imilar time-course responses of drug-metabolizing enzyme mRNAs; little chan ge 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 oltip raz were of similar magnitude and clustered around 4-fold for most enzymes. With the exception of one UGT isozyme (UGT1A1), the elevations in mRNA wer e blocked by prior administration of actinomycin D, indicative of a transcr iption-dependent response. Neither tert-butyl-4-hydroxyanisole nor tert-but ylhydroquinone caused a statistically significant increase in any mRNA exam ined at any time point.