title: Chronic Treatment with Isoniazid Causes Protoporphyrin IX Accumulation in Mouse Liver.
abstract: Isoniazid (INH) can cause hepatotoxicity. In addition, INH is contraindicated in patients suffering from porphyrias. Our metabolomic analysis revealed that chronic treatment with INH in mice causes a hepatic accumulation of protoporphyrin IX (PPIX). PPIX is an intermediate in the heme biosynthesis pathway, and it is also known as a hepatotoxin. We further found that INH induces delta-aminolevulinate synthase 1 (ALAS1), the rate-limiting enzyme in heme biosynthesis. We also found that INH downregulates ferrochelatase (FECH), the enzyme that converts PPIX to heme. In summary, this study illustrated that chronic treatment with INH causes PPIX accumulation in mouse liver in part through ALAS1 induction and FECH downregulation. This study also highlights that drugs can disrupt the metabolic pathways of endobiotics and increase the risk of liver damage.
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Madhav
authors.initials: M
authors.lastname: Sachar
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine , Houston, Texas 77030, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D007538:Isoniazid / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011524:Protoporphyrins / Q000097:blood / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D011524:Protoporphyrins; C028025:protoporphyrin IX; D007538:Isoniazid