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Research ArticleToxicology

Chimeric TK-NOG Mice: A Predictive Model for Cholestatic Human Liver Toxicity

Dan Xu, Manhong Wu, Sachiko Nishimura, Toshihiko Nishimura, Sara A. Michie, Ming Zheng, Zicheng Yang, Alexander John Yates, Jeffrey S. Day, Kathleen M. Hillgren, Saori Takedai Takeda, Yuan Guan, Yingying Guo and Gary Peltz
Journal of Pharmacology and Experimental Therapeutics February 2015, 352 (2) 274-280; DOI: https://doi.org/10.1124/jpet.114.220798
Dan Xu
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.)
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Manhong Wu
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.)
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Sachiko Nishimura
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.)
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Toshihiko Nishimura
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.)
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Sara A. Michie
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.)
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Ming Zheng
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.)
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Zicheng Yang
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.)
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Alexander John Yates
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.)
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Jeffrey S. Day
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.)
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Kathleen M. Hillgren
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.)
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Saori Takedai Takeda
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.)
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Yuan Guan
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.)
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Yingying Guo
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.)
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Gary Peltz
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.)
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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.

Footnotes

    • Received October 16, 2014.
    • Accepted November 20, 2014.
  • D.X. and M.W. are cofirst authors of this paper.

  • This work was supported by a transformative R01 award from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 1R01-DK0909921]. This work was also partially supported by Eli Lilly and Company through the Lilly Research Award Program.

  • dx.doi.org/10.1124/jpet.114.220798.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 2
1 Feb 2015
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Research ArticleToxicology

A Predictive Model for Human Cholestatic Liver Toxicity

Dan Xu, Manhong Wu, Sachiko Nishimura, Toshihiko Nishimura, Sara A. Michie, Ming Zheng, Zicheng Yang, Alexander John Yates, Jeffrey S. Day, Kathleen M. Hillgren, Saori Takedai Takeda, Yuan Guan, Yingying Guo and Gary Peltz
Journal of Pharmacology and Experimental Therapeutics February 1, 2015, 352 (2) 274-280; DOI: https://doi.org/10.1124/jpet.114.220798

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Research ArticleToxicology

A Predictive Model for Human Cholestatic Liver Toxicity

Dan Xu, Manhong Wu, Sachiko Nishimura, Toshihiko Nishimura, Sara A. Michie, Ming Zheng, Zicheng Yang, Alexander John Yates, Jeffrey S. Day, Kathleen M. Hillgren, Saori Takedai Takeda, Yuan Guan, Yingying Guo and Gary Peltz
Journal of Pharmacology and Experimental Therapeutics February 1, 2015, 352 (2) 274-280; DOI: https://doi.org/10.1124/jpet.114.220798
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