title: Humanized thymidine kinase-NOG mice can be used to identify drugs that cause animal-specific hepatotoxicity: a case study with furosemide.
abstract: Interspecies differences have limited the predictive utility of toxicology studies performed using animal species. A drug that could be a safe and effective treatment in humans could cause toxicity in animals, preventing it from being used in humans. We investigated whether the use of thymidine kinase (TK)-NOG mice with humanized livers could prevent this unfortunate outcome (i.e., "rescue" a drug for use in humans). A high dose of furosemide is known to cause severe liver toxicity in mice, but it is a safe and effective treatment in humans. We demonstrate that administration of a high dose of furosemide (200 mg/kg i.p.) causes extensive hepatotoxicity in control mice but not in humanized TK-NOG mice. This interspecies difference results from a higher rate of production of the toxicity-causing metabolite by mouse liver. Comparison of their survival curves indicated that the humanized mice were more resistant than control mice to the hepatotoxicity caused by high doses of furosemide. In this test case, humanized TK-NOG mouse studies indicate that humans could be safely treated with a high dose of furosemide.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.).
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.).
authors.forename: Sara A
authors.initials: SA
authors.lastname: Michie
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.).
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.).
authors.forename: Saori
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.).
authors.forename: Manhong
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.Z., M.W., G.P.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); and In Vivo Sciences International, Sunnyvale, California (S.T.) gpeltz@stanford.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005665:Furosemide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D022781:Hepatocytes / Q000473:pathology* / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis; D013045:Species Specificity; D013937:Thymidine Kinase / Q000235:genetics*; D014018:Tissue Distribution
chemical_list: D005665:Furosemide; D013937:Thymidine Kinase