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.

Functional Integrity of the Chimeric (Humanized) Mouse Liver: Enzyme Zonation, Physiologic Spaces, and Hepatic Enzymes and Transporters

“…For human drug metabolism, the model facilitates the administration of metabolites that are identified as culprits of toxicity/activity, as required in new drugdiscovery processes. The preparation serves as useful preclinical tools for drug-drug interactions (Jaiswal et al, 2014), and for drug-induced liver injury (DILI) studies on troglitazone (Barnes et al, 2014;Samuelsson et al, 2014), bosentin (Xu et al, 2015), and fialuridine (Xu et al, 2014).…”

Humanized Mouse Models of Clinical Disease

“…The toxicity of Furosemide is reduced in the TK-NOG mice, similar to what is seen in humans (87). Human liver chimeric TK-NOG mice have also been used to model cholestatic liver toxicity induced by bosentan, which is not seen in control mice (89). Finally, Fah null Rag2 null IL2rg null mice were engrafted with hepatocytes obtained from a donor with familial hypercholesterolaemia.…”

“…The mice developed hypercholesterolaemia and human cholesteryl ester transfer protein as well as apolipoprotein A, which are not found in normal mice, were present in the serum. Replacement of the low-density lipoprotein receptor by AAV9-based gene therapy restored normal lipoprotein profiles, showing that this model could also be used to test gene therapy treatments for this disease (89). …”

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

“…These mice respond to selective induction of ligands for humanspecific nuclear receptors (Katoh et al, 2005a;Emoto et al, 2008;Sanoh and Ohta, 2014). In addition, h-chimeric liver mouse models have been used to study preclinical drugdrug interactions (Jaiswal et al, 2014) and drug-induced liver injury stemming from troglitazone (Barnes et al, 2014;Samuelsson et al, 2014), bosentan (Xu et al, 2015), and fialuridine (Xu et al, 2014), and have provided an essential in vivo safety testing tool for potential human toxic metabolites (Strom et al, 2010;Cohen, 2014;Kitamura and Sugihara, 2014;Xu et al, 2015).…”