Effect of 1-benzylimidazole on cytochromes P-450 induction and on the activities of epoxide hydrolases and UDP-glucuronosyltransferases in rat liver.
The influence of 1-benzylimidazole on the activities of hepatic monooxygenases cytochromes P-450 dependent, epoxide hydrolases and UDP-glucuronosyltransferases was investigated in male Wistar rats. Several doses (25, 75 and 100 mg/kg/day) were administered gastrically during 5 days in order to evaluate the dose-related induction. The treatment caused a dose-dependent hepatomegaly. 1-Benzylimidazole decreased the plasma level in triglycerides by 60-70%; by contrast the cholesterol content was not changed during the time course of the experiment. Lauric acid hydroxylase, benzphentamine N-demethylase, 7-ethoxyresorufin O-deethylase, 7-ethoxycoumarin O-deethylase activities were increased 3.5-, 4-, 13- and 46-fold, respectively with the highest dose. By immunoblotting, an enhancement in the protein bands corresponding to cytochromes P-450c and P-450b could be simultaneously observed, whatever the dose administered, thus suggesting an induction process. However, 1-benzylimidazole failed to bind with high affinity to the cytosolic Ah receptor. On the other hand, measurement of the activity of the microsomal epoxide hydrolase with benzo(a)pyrene-4,5-oxide as substrate and quantitation of the enzyme protein by immunoassay revealed that the increase in the activity after treatment with the compound was the result of enzyme activation only. By contrast, cytosolic epoxide hydrolase was not affected by 1-benzylimidazole. This compound also stimulated three distinct forms of UDP-glucuronosyltransferase. The activities towards 4-methylumbelliferone, 1-naphthol, morphine or a monoterpenoid alcohol, nopol, supported by two different isozymes were significantly increased only with the highest dose; meanwhile bilirubin glucuronidation was 2-fold enhanced, whatever the dose used. These observations emphasize the variety of the effects of 1-benzylimidazole on drug-metabolizing enzymes.
Magdalou
J
J
Centre du Médicament, Faculté des Sciences Pharmaceutiques et Biologiques, U.A. C.N.R.S. No. 597, Nancy, France.
Totis
M
M
Boiteux-Antoine
A F
AF
Fournel-Gigleux
S
S
Siest
G
G
Schladt
L
L
Oesch
F
F
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D007093:Imidazoles; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D014280:Triglycerides; D001564:Benzo(a)pyrene; C017062:1-benzylimidazole; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D014453:Glucuronosyltransferase; D004851:Epoxide Hydrolases