Renbin Huang, Hiroyasu Okuno, Masashi Takasu, Yasuko Shiozaki and Kyoichi Inoue
Third Department of Internal Medicine, Kansai Medical University, Fumizono-cho 10-15, Moriguchi, Osaka 570, Japan
Abstract: Rifampicin conferred significant protection against carbon tetrachloride (CCI4)-induced liver injury. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were not markedly altered and only hepatocellular fatty degeneration was found in mice pretreated with rifampicin (200 mg/kg), whereas severe centrilobular necrosis was observed and serum ALT and AST activities were as high as 281 and 271 I.U./l, respectively, in the control group following administration of CCI4 (400 microl/kg). The contents and activities of microsomal drug-metabolizing enzymes in rifampicin-pretreated animals were also much higher than those of the controls. CCl4-mediated malondialdehyde (MDA) formation was increased in rifampicin-treated liver microsomes, demonstrating that rifampicin was capable of increasing the NADPH-dependent metabolism of CCl4 catalyzed by P-450 2E1 to produce free radicals. However, MDA formation was obviously depressed by rifampicin at varying concentrations 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 metabolism of CCl4 and aniline hydroxylation were not suppressed in the presence of rifampicin in this systems, suggesting that rifampicin did not influence the biotransformation of CCl4 by P-450 2E1 in vitro. Therefore, the protective effect of rifampicin against CCl4 hepatotoxicity appeared to result from the direct inhibition of lipid peroxidation generated by CCl4-derived free radicals.
Keywords: Rifampicin, Carbon tetrachloride, Cytochrome P-450, Liver injury, Malondialdehyde
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