title: Identification and categorization of liver toxicity markers induced by a related pair of drugs.
abstract: Drug-induced liver injury (DILI) is the primary adverse event that results in the withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in the pre-clinical or clinical phases of drug development. This paper presents an approach for identifying potential liver toxicity genomic biomarkers from a liver toxicity biomarker study involving the paired compounds entacapone ("non-liver toxic drug") and tolcapone ("hepatotoxic drug"). Molecular analysis of the rat liver and plasma samples, combined with statistical analysis, revealed many similarities and differences between the in vivo biochemical effects of the two drugs. Six hundred and ninety-five genes and 61 pathways were selected based on the classification scheme. Of the 61 pathways, 5 were specific to treatment with tolcapone. Two of the 12 animals in the tolcapone group were found to have high ALT, AST, or TBIL levels. The gene Vars2 (valyl-tRNA synthetase 2) was identified in both animals and the pathway to which it belongs, the aminoacyl-tRNA biosynthesis pathway, was one of the three most significant tolcapone-specific pathways identified.
authors.affiliation: Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA; E-Mail: ching-wei.chang@fda.hhs.gov.
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: Wade M
authors.initials: WM
authors.lastname: Hines
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001577:Benzophenones / Q000737:chemistry / Q000633:toxicity*; D001663:Bilirubin / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D053263:Gene Regulatory Networks; D008099:Liver / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000633:toxicity*; D009596:Nitrophenols / Q000737:chemistry / Q000633:toxicity*; D012346:RNA, Transfer, Amino Acyl / Q000096:biosynthesis; D051381:Rats; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D015415:Biomarkers; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D012346:RNA, Transfer, Amino Acyl; C071192:entacapone; D000077867:Tolcapone; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin