title: Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation.
abstract: The mechanisms by which acute administration of methapyrilene, an H(1)-receptor antihistamine causes periportal necrosis to rats are unknown. This study investigated the role of the hepato-biliary system in methapyrilene hepatotoxicity following daily administration of 150 mg/kg per day over 3 consecutive days. Biliary metabolites of methapyrilene were tentatively identified. In male Han Wistar rats administration of methapyrilene significantly increased hepatic reduced glutathione (GSH) to 140% of control levels 24 h following the last dose. There were no significant changes in the activities of glutathione-related enzymes, glutathione peroxidase (GPx) and reductase (GSH), glutathione S-transferase (GST), and gamma-glutamyl cysteine synthetase (gamma-GCS) over 3 days of methapyrilene administration. Methapyrilene treatment resulted in no significant increase in excretion of biliary oxidized glutathione (GSSG), a sensitive marker of oxidative stress in vivo, following the third dose. [3H]Methapyrilene-derived radioactivity was detected in bile, to a greater extent than in feces, indicating that methapyrilene and/or metabolites underwent enterohepatic recirculation. Cannulation and exteriorization of the bile duct (to interrupt enterohepatic recirculation) afforded some protection against the hepatotoxicity, assessed by clinical chemistry and histopathology. Liquid chromatography-mass spectrometry (LC-MS) analysis of bile indicated the presence of unmetabolized methapyrilene, methapyrilene O-glucuronide and desmethyl methapyrilene O-glucuronide. These data demonstrate that acute methapyrilene hepatotoxicity in vivo is not a consequence of GSH depletion, or oxidative stress, but that enterohepatic recirculation of biliary metabolites may be important. Progressive exposure to non-oxidizing, reactive metabolic intermediates may be responsible for hepatotoxicity.
authors.affiliation: Department of Toxicology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, EC1M 6BQ, London, UK. ratra@nature.berkeley.edu
authors.forename: G S
authors.initials: GS
authors.lastname: Ratra
authors.forename: C J
authors.initials: CJ
authors.lastname: Powell
authors.forename: B K
authors.initials: BK
authors.lastname: Park
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: S
authors.initials: S
authors.lastname: Cottrell
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D005243:Feces; D020719:Glucuronides / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D008701:Methapyrilene / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium
chemical_list: D020719:Glucuronides; D014316:Tritium; D008701:Methapyrilene; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D005978:Glutathione