SUPPRESSION OF LIVER CYTOCHROME-P450 BY ALPHA-HEDERIN - RELEVANCE TO HEPATOPROTECTION

This study was designed to determine the protective effects of alpha-h ederin on chemical-induced liver injury in CF-1 mice and to evaluate c ytochrome P450 suppression by alpha-hederin as a means of protection. alpha-Hederin pretreatment (30 mu mol/kg, sc x 3 days) protected mice from acetaminophen-, bromobenzene-, carbon tetrachloride-, furosemide- , and thioacetamide-induced liver injury, without affecting the hepato toxicity of chloroform and dimethylnitrosamine. To examine the role of P450 in hepatoprotection by alpha-hederin, liver microsomes were prep ared 24 hr following the last dose of alpha-hederin treatment (10 and 30 mu mol/kg, sc x 3 days). Treatment of mice with alpha-hederin produ ced a dose-dependent suppression of liver cytochrome P450 (30-50%) and cytochrome b(5) (20-30%) levels, as well as NADPH-cytochrome c reduct ase activity (15-25%). alpha-Hederin treatment also decreased the acti vities of P450 enzymes, such as 7-ethoxyresorufin O-dealkylation (65%) , 7-pentoxyresorufin O-dealkylation (50%), coumarin 7-hydroxylation (4 0%), 7-ethoxycoumarin O-deethylation (45%), caffeine N-3-demethylation (30-50%), chlorzoxazone 6-hydroxylation (35-55%), and the oxidation o f testosterone to 2 alpha-, 6 alpha-, 15 alpha-, 15 beta-, 16 alpha-, 16 beta-, and 18/12 alpha-hydroxyltestosterone, androstenedione, and 6 -dehydroxytestosterone (25-60%). Consistent with these observations, t he levels of CYP1A, CYP2A, and CYP3A enzymes were also suppressed, as determined by immunoblotting with antibodies against rat P450 enzymes. These results demonstrate that treatment of mice with alpha-hederin d ecreases the levels and activities of several P450 enzymes. The suppre ssion of P450 appears to be one of mechanisms by which alpha-hederin p rotects mice from the hepatotoxicity of some chemicals. (C) 1995 Acade mic Press, Inc.