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

Rifampicin and isoniazid co–therapy frequently causes liver injury in humans. A pregnane X receptor–humanized mouse model revealed that rifampicin and isoniazid co–treatment causes accumulation of protoporphyrin IX, an endogenous hepatotoxin, in the liver via a pregnane X receptor–mediated alteration of heme biosynthesis pathway. These results provide novel insight into the mechanism of rifampicin and isoniazid–induced liver injury that may be applied to clinical management of the hepatotoxicity associated with tuberculosis chemotherapy.