A novel mechanism underlies the hepatotoxicity of pyrazinamide

Tung Yuan Shih, Chien Yi Pai, Ping Yang, Wen Liang Chang, Ning Chi Wang, Oliver Yoa Pu Hu

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Abstract

Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA- and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P<0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P<0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.

Original languageEnglish
Pages (from-to)1685-1690
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number4
DOIs
Publication statusPublished - Apr 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Shih, T. Y., Pai, C. Y., Yang, P., Chang, W. L., Wang, N. C., & Hu, O. Y. P. (2013). A novel mechanism underlies the hepatotoxicity of pyrazinamide. Antimicrobial Agents and Chemotherapy, 57(4), 1685-1690. https://doi.org/10.1128/AAC.01866-12