title: A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.
abstract: Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmaxlevel of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tamai
authors.forename: Takuma
authors.initials: T
authors.lastname: Iguchi
authors.forename: Noriyo
authors.initials: N
authors.lastname: Niino
authors.forename: Kei
authors.initials: K
authors.lastname: Mikamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Sakurai
authors.forename: Ayako
authors.initials: A
authors.lastname: Sayama
authors.forename: Hitomi
authors.initials: H
authors.lastname: Shimoda
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mori
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007097:Imines / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D035683:MicroRNAs / Q000097:blood; D010641:Phenotype
chemical_list: D016227:Benzoquinones; D007097:Imines; D035683:MicroRNAs; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine