Dataset Information

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

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.

SUBMITTER: Zhao H

PROVIDER: S-EPMC6062402 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a <sup>1</sup>H NMR based metabolomics approach.

Zhao He H Si Zhi-Hong ZH Li Ming-Hui MH Jiang Lei L Fu Yong-Hong YH Xing Yue-Xiao YX Hong Wei W Ruan Ling-Yu LY Li Pu-Ming PM Wang Jun-Song JS

Toxicology research 20161005 1

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 <sup>1</sup>H NMR-based me ...[more]

PMID: 30090474

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Project description:IntroductionErythromycin (ERY) is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism.ObjectiveTo establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using 1H NMR based serum metabolomics.ExperimentalFourteen male rats were randomly divided into two groups (n = 7 in each group): control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D 1H CPMG and diffusion-edited nuclear magnetic resonance (NMR) spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group.ResultsThe serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a) increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b) decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a) decreased TCA cycle activity and enhanced fatty acid oxidation, (b) dysfunction of lipid and amino acid metabolism and (c) oxidative stress.Conclusion and recommendationsErythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new drug-formulations.

Dataset Information

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

Publications

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a <sup>1</sup>H NMR based metabolomics approach.

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Dataset Information

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

Publications

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a <sup>1</sup>H NMR based metabolomics approach.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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