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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.).
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.
