title: Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy.
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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Laiyou
authors.initials: L
authors.lastname: Wang
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Iván L
authors.initials: IL
authors.lastname: Csanaky
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination / Q000009:adverse effects; D006418:Heme / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D011524:Protoporphyrins / Q000032:analysis / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000995:Antitubercular Agents; D000077297:Pregnane X Receptor; D011524:Protoporphyrins; D011987:Receptors, Steroid; D006418:Heme; C028025:protoporphyrin IX; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D007538:Isoniazid; D012293:Rifampin