title: Xanthine oxidase inhibition by allopurinol increases in vitro pyrazinamide-induced hepatotoxicity in HepG2 cells.
abstract: Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in vitro pyrazinamide toxicity in HepG2 cells, which suggests that the hydroxy metabolites of pyrazinamide are probably not fully responsible for pyrazinamide-induced toxicity, and that pyrazinoic acid and pyrazinamide are involved in pyrazinamide toxicity.
authors.affiliation: Department of Pulmonary Diseases, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. A.Tostmann@ulc.umcn.nl
authors.forename: Alma
authors.initials: A
authors.lastname: Tostmann
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
authors.forename: P N Richard
authors.initials: PN
authors.lastname: Richard
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D011718:Pyrazinamide / Q000633:toxicity*; D018709:Statistics, Nonparametric; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011718:Pyrazinamide; D000493:Allopurinol; D014969:Xanthine Oxidase