Does CYP2E1 play a major role in the aggravation of isoniazid toxicity by rifampicin in human hepatocytes?
Isoniazid and rifampicin are first-line anti-tubercular drugs. In a recent paper, Shen et al. provided interesting findings that rifampicin 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-Nitrophenol hydroxylase (4-NP) activity was the only probe of CYP2E1 activity used in the paper. The authors presented data showing that rifampicin 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-specific 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-quantitative 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 rifampicin in human hepatocytes.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China. yuelehe@yahoo.com.cn
Jiang
J
Yue
Renxiu
R
Peng
D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007538:Isoniazid / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
D000995:Antitubercular Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D007538:Isoniazid