Abstract
Rifampicin and pyrogallol, besides beneficial effects, elicit hepatotoxicity in experimental animals and humans. The present investigation was undertaken to elucidate the role of drug/toxicant-metabolizing enzymes in rifampicin- and pyrogallol-induced hepatotoxicity and the effect of silymarin, a herbal antioxidant, on rifampicin- and pyrogallol-induced alterations in mouse liver. Male Swiss albino mice were treated intraperitoneally with and without rifampicin (20 mg/kg) and/or pyrogallol (40 mg/kg) for 1, 2, 3 and 4 weeks. In some experiments, animals were treated with silymarin (40 mg/kg), 2 h prior to rifampicin and/or pyrogallol. The differential expression and catalytic activity of cytochrome P-450 ( CYP) 1A1, CYP1A2 and CYP2E1, the activity of glutathione- S-transferase, glutathione peroxidase and glutathione reductase, and lipid peroxidation were measured in the liver of control and treated groups. CYP1A1 expression and catalytic activity were not altered following individual or combinational treatment. A significant augmentation in the expression and activity of CYP1A2 and CYP2E1 was observed following pyrogallol and rifampicin + pyrogallol treatment; however, rifampicin exhibited a significant induction of CYP2E1 only. Attenuation of glutathione- S-transferase, glutathione reductase and glutathione peroxidase activities and augmentation of lipid peroxidation were observed following rifampicin and/or pyrogallol treatment and a cumulative effect was seen when the two drugs were administered in combination. Silymarin restored the rifampicin- and/or pyrogallol-induced alterations in the expression and activity of CYP1A2 and CYP2E1, the activity of glutathione- S-transferase, glutathione reductase, and glutathione peroxidase, and lipid peroxidation. The results demonstrate the role of CYP1A2, CYP2E1, glutathione- S-transferase, glutathione reductase and glutathione peroxidase in rifampicin- and pyrogallol-induced hepatotoxicity and provide evidence for the involvement of silymarin in attenuation of drug-induced hepatotoxicity.
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