4.5 Article

Bile acids, lipid and purine metabolism involved in hepatotoxicity of first-line anti-tuberculosis drugs

Journal

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
Volume 16, Issue 6, Pages 527-537

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/17425255.2020.1758060

Keywords

Metabolomics; first-line anti-tuberculosis drugs; hepatotoxicity; FXR; bile acid

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Objectives Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination. Methods UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway. Results In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR(-/-)mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH. Conclusion ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.

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