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Tuberculosis is a global health threat that affects millions of people every year, and treatment-limiting toxicity remains a considerable source of treatment failure. Recent reports have characterized the nature of <i>hPXR</i>-mediated hepatotoxicity and the systemic toxicity of antitubercular drugs. The antitubercular drug isoniazid plays a role in such pathologic states as acute intermittent porphyria, anemia, hepatotoxicity, hypercoagulable states (deep vein thrombosis, pulmonary embolism, or ischemic stroke), pellagra (vitamin B₃ deficiency), peripheral neuropathy, and vitamin B₆ deficiency. However, the mechanisms by which isoniazid administration leads to these states are unclear. To elucidate the mechanism of rifampicin- and isoniazid-induced liver and systemic injury, we performed tandem mass tag mass spectrometry-based proteomic screening of <i>mPxr</i>^−/− and <i>hPXR</i> mice treated with combinations of rifampicin and isoniazid. Proteomic profiling analysis suggested that the <i>hPXR</i> liver proteome is affected by antitubercular therapy to disrupt [Fe–S] cluster assembly machinery, [2Fe–2S] cluster-containing proteins, cytochrome P450 enzymes, heme biosynthesis, homocysteine catabolism, oxidative stress responses, vitamin B₃ metabolism, and vitamin B₆ metabolism. These novel findings provide insight into the etiology of some of these processes and potential targets for subsequent investigations. Data are available via ProteomeXchange with identifier PXD019505.