title: Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism.
abstract: One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach.
authors.affiliation: AstraZeneca, DMPK, Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Simone H
authors.initials: SH
authors.lastname: Stahl
authors.affiliation: AstraZeneca, DMPK, Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Yates
authors.affiliation: GlaxoSmithKline, Investigative Preclinical Toxicology, Park Road, Ware, Hertfordshire SG12 0DP, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Nicholls
authors.affiliation: FRAME, Russell & Burch House, North Sherwood Street, Nottingham NG1 4EE, UK.
authors.forename: J Gerry
authors.initials: JG
authors.lastname: Kenna
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK. Electronic address: i.wilson@imperial.ac.uk.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
mesh_terms: D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D014116:Toxicology / Q000379:methods; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D015415:Biomarkers; D015262:Xenobiotics; D000082:Acetaminophen; D005978:Glutathione