Effect of oleanolic acid on hepatic toxicant-activating and detoxifying systems in mice.
We have previously shown that oleanolic acid (OA) protects mice against the hepatotoxicity of carbon tetrachloride, acetaminophen, bromobenzene, thioacetamide, furosemide, phalloidin, colchicine, cadmium, D-galactosamine and endotoxin. This study was designed to examine whether OA modulates hepatic toxicant-activating and detoxifying systems as a means of protection. Mice were treated with OA (100 and 200 mumol/kg s.c.) for 3 days, and liver microsomes and cytosols were prepared 24 hr after the last dose. OA produced a dose-dependent reduction in liver microsomal cytochrome P450 (P450) levels (25-37%) and cytochrome b5 (15-21%) content, but had no effect on NADPH-cytochrome c reductase activity. OA treatment also decreased several P450 enzyme activities, such as coumarin 7-hydroxylation (45%), 7-pentoxyresorufin O-dealkylation (35%), 7-ethoxyresorufin O-dealkylation (25%) and chlorzoxazone 6-hydroxylation (20%). Treatment of mice with OA decreased caffeine N3-demethylation (40%), but had no effect on caffeine 8-hydroxylation. OA treatment decreased testosterone 6 alpha- and 15 alpha-hydroxylation (40-50%) and androstenedione formation (35%), but slightly increased testosterone 1 alpha/beta-, 2 beta- and 6 beta-hydroxylation. Consistent with enzyme activities, OA decreased the amounts of mouse liver CYP1A and CYP2A enzymes, but had no appreciable effect on CYP3A enzymes, as determined by immunoblotting with antibodies against rat P450 enzymes. OA treatment slightly increased liver glutathione (GSH) content and the activity of GSH S-transferases toward 1-chloro-2,4-dinitrobenzene, but had no effect on GSH peroxidase and GSH reductase. The activities of superoxide dismutase and DT-diaphorase were unaffected by OA treatment. At the high dose of OA, catalase activity was decreased by 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000187:drug effects*; D002110:Caffeine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009828:Oleanolic Acid / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism
D002110:Caffeine; D009828:Oleanolic Acid; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione