Suppression of Liver Cytochrome P450 by α-Hederin: Relevance to Hepatoprotection

Abstract

This study was designed to determine the protective effects of α-hederin on chemical-induced liver injury in CF-1 mice and to evaluate cytochrome P450 suppression by α-hederin as a means of protection. α-Hederin pretreatment (30 μmol/kg, sc × 3 days) protected mice from acetaminophen-, bromobenzene-, carbon tetrachloride-, furosemide-, and thioacetamide-induced liver injury, without affecting the hepatotoxicity of chloroform and dimethylnitrosamine. To examine the role of P450 in hepatoprotection by α-hederin, liver microsomes were prepared 24 hr following the last dose of α-hederin treatment (10 and 30 μmol/kg, sc × 3 days). Treatment of mice with α-hederin produced a dose-dependent suppression of liver cytochrome P450 (30-50%) and cytochrome b5 (20-30%) levels, as well as NADPH-cytochrome c reductase activity (15-25%). α-Hederin treatment also decreased the activities of P450 enzymes, such as 7-ethoxyresorufin O-dealkylation (65%), 7-pentoxyresorufin O-dealkylation (50%), coumarin 7-hydroxylation (40%), 7-ethoxycoumarin O-deethylation (45%), caffeine N3-demethylation (30-50%), chlorzoxazone 6-hydroxylation (35-55%), and the oxidation of testosterone to 2 α-, 6 α-, 15 α-, 15 β-, 16 α-, 16 β-, and 18/12 α-hydroxyltestosterone, androstenedione, and 6-dehydroxytestosterone (25-60%). Consistent with these observations, the 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 α-hederin decreases the levels and activities of several P450 enzymes. The suppression of P450 appears to be one of mechanisms by which α-hederin protects mice from the hepatotoxicity of some chemicals.