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Published on: September 15, 2018
Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity
Dan Xu1, Manhong Wu1, Sachiko Nishimura1
1Department 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.).
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.
Insights
Humanized TK-NOG mice accurately predict drug-induced liver injury (DILI) in humans. These mice show human-like drug metabolism and toxicity, improving preclinical safety assessments for new drugs.
Area of Science:
- Pharmacology
- Toxicology
- Hepatology
Background:
- Drug-induced liver injury (DILI) in humans is often not predicted by animal models due to interspecies differences in drug metabolism and disposition.
- Bosentan, a drug for pulmonary artery hypertension, caused unexpected cholestatic liver toxicity in humans, which was not identified in preclinical animal studies.
Purpose of the Study:
- To evaluate the utility of NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers for predicting human DILI.
- To assess the humanized liver profile of biliary excretion and drug retention in TK-NOG mice.
- To investigate the development of liver toxicity in TK-NOG mice following bosentan administration.
Main Methods:
- Humanized TK-NOG mice were utilized to study biliary excretion of cefmetazole using in situ perfusion studies.
- TK-NOG mice with humanized livers were treated with bosentan at varying doses (160, 32, or 6 mg/kg/day) for 1 week.
- Control mice were treated with bosentan for 1 month to compare toxicity development.
Main Results:
- Humanized TK-NOG mice exhibited a humanized profile of biliary drug excretion, attributed to interspecies differences in biliary transport and liver retention.
- Readily detectable cholestatic liver injury developed in TK-NOG mice with humanized livers after 1 week of bosentan treatment.
- The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice closely mirrored those observed in human subjects, unlike in control mice.
Conclusions:
- Humanized TK-NOG mice serve as a valuable preclinical model for predicting human DILI.
- This model can improve drug safety assessments by identifying potential hepatotoxicity earlier and more accurately.
- Implementing humanized TK-NOG mice in preclinical toxicology studies could significantly enhance overall drug safety and public health outcomes.
