PROTECTIVE EFFECT OF RIFAMPICIN AGAINST ACUTE LIVER-INJURY INDUCED BYCARBON-TETRACHLORIDE IN MICE

Rifampicin conferred significant protection against carbon tetrachlori de (CCl4)-induced liver injury. Serum alanine transaminase (ALT) and a spartate transaminase (AST) activities were not markedly altered and o nly hepatocellular fatty degeneration was found in mice pretreated wit h rifampicin (200 mg/kg), whereas severe centrilobular necrosis was ob served surd serum ALT and AST activities were as high as 281 and 271 I .U./l, respectively, in the control group following administration of CCl4 (400 mu l/kg). The contents and activities of microsomal drug-met abolizing enzymes in rifampicin-pretreated animals were also much high er than those of the controls. CCl4-mediated. malondialdehyde (MDA) fo rmation was increased in rifampicin-treated liver microsomes, demonstr ating that rifampicin was capable of increasing the NADPH-dependent me tabolism of CCl4 catalyzed by P-450 2E1 to produce free radicals. Howe ver, MDA formation was obviously depressed by rifampicin at varying co ncentrations from 2 to 32 x 10(-6) M in an in vitro cytochrome P-450 ( P-450) enzyme system. On the other hand, NADPH oxidation in the metabo lism of CCl4 and aniline hydroxylation were not suppressed in the pres ence of rifampicin in this systems, suggesting that rifampicin did not influence the biotransformation of CCl4 by P-450 2E1 in vitro. Theref ore, the protective effect of rifampicin against CCl4 hepatotoxicity a ppeared to result from the direct inhibition of lipid peroxidation gen erated by CCl4-derived free radicals.