S31 Utility of Humanized Liver Mouse Model in Evaluation of Mitochondrial Transporters-Associated Hepatotoxicity

Yingying Guo , Division of Drug Disposition, Eli Lilly and Company, Indianapolis, IN
In drug discovery and development, the inter-species difference in the structure and abundance of enzymes and transporters has challenged our ability to predict drug elimination, distribution, efficacy and toxicity prior to human testing. A recently-developed humanized liver mouse model (TK-NOG) has gene expression patterns (including many human drug metabolizing enzymes and transporters) characteristic of mature human liver. This presentation examines how TK-NOG mice with humanized livers can improve understanding of drugs. Specifically, the humanized liver TK-NOG mice mirror human liver responses induced by agents that have known inter-species differences in hepatotoxicity with involvement of mitochondrial transporters. The humanized liver mouse model is a promising preclinical tool in detecting human specific hepatotoxicity in a functioning organism.