Abstract
Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.
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Acknowledgements
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant number DK090305) and the National Cancer Institute Intramural Research Program. We thank M. Montello for editing the manuscript.
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F.L., J.L., J.C., L.W., T.M., I.L.C. and X.M. performed the experiments. C.D.K. and F.J.G. contributed to the scientific discussion and manuscript editing. X.M. and F.L. conceived the project and wrote the manuscript.
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Li, F., Lu, J., Cheng, J. et al. Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy. Nat Med 19, 418–420 (2013). https://doi.org/10.1038/nm.3104
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DOI: https://doi.org/10.1038/nm.3104
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