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Aim: Biochemical characterization of long-term toxic manifestations of anti-tubercular (anti-TB) drugs – rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) – individually and in two combinations: (i) RIF + INH, and (ii) RIF + INH + PZA in Wistar rats. Methods: Animals received anti-TB drugs – alone or in combination – once daily p.o. for up to 90 days (doses, in mg/kg: RIF, 250; INH, 50; PZA, 100). Assays for alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin (serum) and lipid peroxidation (LPO), glutathione (GSH), glutathione peroxidase (GPx), catalase, Na+K+-ATPase and CYP 2E1 (liver) were performed to assess liver toxicity. Clinical biochemistry was done by commercial kits. Determinations were made at 0, 15, 30 and 90 days of treatment schedule. Results: Anti-TB drugs-treated animals showed abnormal rises or falls (>1.5–2 fold) in the serum/liver parameters. Mild hyperlipidemia, hypercholesterolemia and hyperuricemia were the other pathologies. Of all the treated groups, INHalone or in combination with other drugs produced a progressive enhancement of toxicity over 15–90 days. The in vivo results were further supported by in vitro results (MTT assay, GSH and LPO) in primary cultures of rat hepatocyte. Results indicated that anti-TB drugs in combination: (i) caused membrane damage resulting in leakage of ALT, ALP and bilirubin; (ii) caused imbalance in endogenous enzymatic oxidant–antioxidant defense via increased lipid peroxidation and in glutathione homeostasis; and (iii) enhanced the CYP 2E1-mediated bioactivation mechanism. Conclusion: Toxicity manifestations seemed to be heptocytic injury targeted at hepatocytes, bile ducts or sinusoidal cells related to hepatitis and primary biliary cholestasis. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, the biochemical manifestations of liver toxicity caused by co-administration of anti-TB drugs, rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA), in a sub-chronic mode (12 weeks), were investigated. Significant alterations were revealed in (a) increased levels of alanine aminotrasferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) and a high bilirubin content in serum; (b) elevated lipid peroxidation (LPO), intracellular calcium [Ca2+]i and CYP4502EI activity in liver; and (c) decreased glutathione (GSH) content, glutathione peroxidase (GPx) and catalase activities in liver. Silymarin reversed these abnormal alterations. The biochemical changes were supported by histological observations. [Copyright &y& Elsevier]