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Issue 1, 2017
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Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a 1H NMR based metabolomics approach

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Abstract

Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg−1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD+ metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

Graphical abstract: Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a 1H NMR based metabolomics approach

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Publication details

The article was received on 03 Jun 2016, accepted on 04 Oct 2016 and first published on 05 Oct 2016


Article type: Paper
DOI: 10.1039/C6TX00245E
Citation: Toxicol. Res., 2017,6, 17-29
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    Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a 1H NMR based metabolomics approach

    H. Zhao, Z. Si, M. Li, L. Jiang, Y. Fu, Y. Xing, W. Hong, L. Ruan, P. Li and J. Wang, Toxicol. Res., 2017, 6, 17
    DOI: 10.1039/C6TX00245E

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