Rifampicin exacerbates isoniazid‐induced toxicity in human but not in rat hepatocytes in tissue‐like cultures

Abstract

Background and purpose: Rifampicin has been extensively reported to exacerbate the hepatotoxicity of isoniazid in patients with tuberculosis. However, this was controversially claimed by previous reports using rat models. This study evaluated the effect of rifampicin on isoniazid‐induced hepatocyte toxicity by using human and rat hepatocytes in tissue‐like culture. Experimental approach: Hepatocytes in tissue‐like gel entrapment were used to examine isoniazid toxicity, as shown by cell viability, intracellular glutathione content and albumin secretion. For demonstration of the differential effects of rifampicin on human and rat hepatocytes, induction by rifampicin of cytochrome P450 (CYP) 2E1, a major enzyme associated with isoniazid hepatotoxicity, was detected by 4‐nitrocatechol formation and RT‐PCR analysis. Key results: Rifampicin (12 μM) enhanced isoniazid‐induced toxicity in human hepatocytes but not in rat hepatocytes. Enhanced CYP 2E1 enzymic activity and mRNA expression were similarly detected in human hepatocytes but not in rat hepatocytes. Both rat and human hepatocytes in gel entrapment were more sensitive to isoniazid treatment compared with the corresponding hepatocytes in a monolayer culture. Conclusions and implications: The difference in induction of CYP 2E1 by rifampicin between rat and human hepatocytes accounted for the difference in exacerbation of isoniazid hepatocyte toxicity by rifampicin, with more significant toxicity in gel entrapment than in monolayer cultures. Thus, human hepatocytes in tissue‐like cultures (gel entrapment) could be an effective model for hepatotoxicity research in vitro, closer to the in vivo situation. British Journal of Pharmacology (2008) 153, 784–791; doi:10.1038/sj.bjp.0707611; published online 10 December 2007