title: Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.
abstract: Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan (160, 32, or 6 mg/kg per day by mouth), whereas liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Because DILI has become a significant public health problem, drug safety could be improved if preclinical toxicology studies were performed using humanized TK-NOG.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.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.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.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.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.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.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.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.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Zicheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Alexander John
authors.initials: AJ
authors.lastname: Yates
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Day
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Hillgren
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Saori Takedai
authors.initials: ST
authors.lastname: Takeda
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.).
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California (D.X., M.W., T.N., M.Z., Yu.G., G.P.); Center for the Advancement of Health and Bioscience, Sunnyvale, California (S.N., T.N.); Central Institute for Experimental Animals, Kawasaki, Japan (T.N.); Department of Pathology, Stanford University, Stanford, California (S.A.M.); Bruker CAM & LSC7, Fremont, California (Z.Y., A.J.Y.); Department of Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (J.S.D., K.M.H., Yi.G.); and In Vivo Sciences International, Sunnyvale, California (S.T.T.) gpeltz@stanford.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000818:Animals; D000077300:Bosentan; D015311:Cefmetazole / Q000493:pharmacokinetics*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002779:Cholestasis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D006801:Humans; D008657:Metabolic Clearance Rate; D008822:Mice, Transgenic; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution; D019076:Transgenes
chemical_list: D013449:Sulfonamides; D015311:Cefmetazole; D013937:Thymidine Kinase; D015774:Ganciclovir; D000077300:Bosentan