title: The liver toxicity biomarker study phase I: markers for the effects of tolcapone or entacapone.
abstract: The Liver Toxicity Biomarker Study is a systems toxicology approach to discover biomarkers that are indicative of a drug's potential to cause human idiosyncratic drug-induced liver injury. In phase I, the molecular effects in rat liver and blood plasma induced by tolcapone (a "toxic" drug) were compared with the molecular effects in the same tissues by dosing with entacapone (a "clean" drug, similar to tolcapone in chemical structure and primary pharmacological mechanism). Two durations of drug exposure, 3 and 28 days, were employed. Comprehensive molecular analysis of rat liver and plasma samples yielded marker analytes for various drug-vehicle or drug-drug comparisons. An important finding was that the marker analytes associated with tolcapone only partially overlapped with marker analytes associated with entacapone, despite the fact that both drugs have similar chemical structures and the same primary pharmacological mechanism of action. This result indicates that the molecular analyses employed in the study are detecting substantial "off-target" markers for the two drugs. An additional interesting finding was the modest overlap of the marker data sets for 3-day exposure and 28-day exposure, indicating that the molecular changes in liver and plasma caused by short- and long-term drug treatments do not share common characteristics.
authors.affiliation: BG Medicine Inc., Waltham, Massachusetts, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: McBurney
authors.forename: Wade M
authors.initials: WM
authors.lastname: Hines
authors.forename: Linda S
authors.initials: LS
authors.lastname: VonTungeln
authors.forename: Laura K
authors.initials: LK
authors.lastname: Schnackenberg
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Su
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Fan
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.forename: Shelagh A
authors.initials: SA
authors.lastname: Booth
authors.forename: Raji
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Paul L
authors.initials: PL
authors.lastname: Courchesne
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Campbell
authors.forename: Armin
authors.initials: A
authors.lastname: Graber
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Peter
authors.initials: P
authors.lastname: Juhasz
authors.forename: Tricia Y
authors.initials: TY
authors.lastname: Li
authors.forename: Moira D
authors.initials: MD
authors.lastname: Lynch
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Morel
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Plasterer
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Takach
authors.forename: Chenhui
authors.initials: C
authors.lastname: Zeng
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D001798:Blood Proteins / Q000032:analysis; D002396:Catechols / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics; D009570:Nitriles / Q000633:toxicity*; D009596:Nitrophenols / Q000633:toxicity*; D020543:Proteome / Q000032:analysis / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D012107:Research Design; D000077867:Tolcapone; D023382:Toxicity Tests, Acute / Q000379:methods; D036401:Toxicity Tests, Chronic / Q000379:methods
chemical_list: D001577:Benzophenones; D015415:Biomarkers; D001798:Blood Proteins; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D020543:Proteome; C071192:entacapone; D000077867:Tolcapone