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Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy

Nature Medicine volume 19, pages 418–420 (2013)Cite this article

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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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Figure 1: The hepatotoxicity associated with RIF and INH co-treatment is human-PXR dependent.
Figure 2: PPIX accumulation and the liver injury associated with RIF and INH co-therapy.

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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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Author notes

  1. Laiyou Wang

    Present address: Present address: Institute of Chinese Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China.,

Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA

    Feng Li, Jie Lu, Laiyou Wang, Iván L Csanaky, Curtis D Klaassen & Xiaochao Ma

  2. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Jie Cheng, Tsutomu Matsubara & Frank J Gonzalez

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  1. Feng Li
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Contributions

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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Correspondence to Xiaochao Ma.

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The authors declare no competing financial interests.

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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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