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
Jg. Lamb et Mr. Franklin, 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, DRUG META D, 28(9), 2000, pp. 1018-1023
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.