title: [Investigation of Predisposition Biomarkers to Identify Risk Factors for Drug-induced Liver Injury in Humans: Analyses of Endogenous Metabolites in an Animal Model Mimicking Human Responders to APAP-induced Hepatotoxicity].
abstract: Drug-induced liver injury is a main reason of regulatory action pertaining to drugs, including restrictions to clinical indications and withdrawal from the marketplace. Acetaminophen (APAP) is a commonly used and effective analgesic/antipyretic agent and relatively safe drug even in long-term treatment. However, it is known that APAP at therapeutic doses may cause hepatotoxicity in some individuals. Hence great efforts have been made to identify risk factors for APAP-induced chronic hepatotoxicity. We investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model. We employed daytime restricted fed (RF) rats as a modified-nutritional state model for human APAP-induced hepatotoxicity. RF and ad libitum fed (ALF) rats were given APAP at 0, 300, and 500 mg/kg for 3 months. Plasma and urinary glutathione-related metabolomes and liver function parameters were measured during the dosing period. Endogenous metabolites forming at different levels between the RF and ALF rats could be potential predisposition biomarkers for APAP-induced hepatotoxicity. In addition, RF rats were considered a useful model to estimate the contribution of nutritional state of patients to APAP-induced chronic hepatotoxicity. In this article we report our current research focusing on nutritional state as risk factor for APAP-induced chronic hepatotoxicity and our findings of hepatotoxicity biomarkers.
authors.affiliation: Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC.
authors.forename: Akio
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kondo
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Sugai
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001786:Blood Glucose / Q000032:analysis; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000175:diagnosis* / Q000209:etiology*; D004195:Disease Models, Animal; D005508:Food Deprivation / Q000502:physiology; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D009752:Nutritional Status; D019289:Pyruvic Acid / Q000097:blood; D012307:Risk Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D001786:Blood Glucose; D019344:Lactic Acid; D000082:Acetaminophen; D019289:Pyruvic Acid