Nature Medicine 2013-04-01

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

Feng Li, Jie Lu, Jie Cheng, Laiyou Wang, Tsutomu Matsubara, Iván L Csanaky, Curtis D Klaassen, Frank J Gonzalez, Xiaochao Ma

Index: Nat. Med. 19(4) , 418-20, (2013)

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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.