Effect of coadministration of antituberculous drugs on the hepatic drug metabolizing enzymes and oxidative stress in the mouse

Objective: To investigate whether the coadministration of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) was more potent than RMP alone in the induction of drug metabolizing enzymes and the causation of oxidative stress in the mouse. Methods: Male mice were administered intraperitoneally 40 mg RMP or simultaneously 40, 40 and 80 mg INH, RMP and PZA per Kg body weight for 3 days. The livers were homogenized in potassium phosphate buffer containing potassium chloride. Microsomes and 100,000 x g supernatant were prepared by differential centrifugation. Assays of cytochrome P450, NADPH cytochrome c reductase, erythromycin N-demethylase and lipid peroxidation were performed in the microsomes. Assays of glutathione reductase, glutathione peroxidase and catalase were performed in 100,000 x g supernatant. Glutathione was assayed in supernatant from 5% TCA homogenate of the liver specimen. Results: Coadministration of INH, RMP and PZA increased the hepatic microsomal cytochrome P450, lipid peroxidation, the activities of NADPH cytochrome c oxidoreductase, erythromycin N-demethylase, Se-independent glutathione peroxidase and intensified 53.5 and 56 kDa polypeptides in the mouse. RMP increased all these parameters except the activity of selenium independent glutathione peroxidase. However, changes caused in the lipid peroxidation and the activity of erythromycin N-demethylase by coadministration of INH, RMP and PZA were more dramatic as compared to RMP. Both treatments did not alter the hepatic glutathione and activities of glutathione reductase, Se-dependent glutathione peroxidase, superoxide dismutase but decreased the activity of catalase in the mouse. Conclusion: Coadministration of INH, RMP and PZA was more potent in the induction of the hepatic microsomal erythromycin N-demethylase and causation of oxidative stress in the mouse as compared to RMP administration alone.