Does CYP2E1 play a major role in the aggravation of isoniazid toxicity by rifampicin in human hepatocytes?

Abstract

Isoniazid and rifampicin are first-line anti-tubercular drugs. In a recent paper, Shen et al., provided interesting findings that rlfampicin exacerbated isoniazid toxicity in human hepatocytes but not in rat hepatocytes. The main conclusion was that the difference in cytochrome P450 2E1 (CYP2E1) Induction by rifampicin between rat and human hepatocytes accounted for the difference In exacerbation of isoniazid hepatotoxicity by rifampicin. 4-Nltrophenol hydroxylase (4-NP) activity was the only probe of CYP2E1 activity used In the paper. The authors presented data showing that rlfampicin enhanced 4-NP activity and CYP2E1 mRNA expression In human hepatocytes, but not in rat hepatocytes. However, CYP3A also makes a significant contribution to 4-NP activity in humans and rats, which has been confirmed by both CYP3A-speclfic Inducer and inhibitors. Rifampicin is a strong Inducer of human CYP3A; thus, the Increase in 4-NP activity In human hepatocytes could be due to the Induction of CYP3A. Rifampicin did not Increase 4-NP activities in rat hepatocytes, which could reflect a lack of the Induction of rat CYP3A by rifampicin. Additionally, more experiments are needed to support the conclusion that rifampicin Increased CYP2E1 mRNA expression In human hepatocytes because of the small sample size and the limitations of semi-quantltatlve RT-PCR. The study by Shen et al. suggests that another drug-metabolizing enzyme rather than CYP2E1 could be involved In the aggravation of Isoniazid toxicity by rlfampicin In human hepatocytes. © 2009 The British Pharmacological Society All rights reserved.