Mice with Liver Composed of Human Hepatocytes as an Animal Model for Drug Testing

Katsutoshi      Yoshizato; Chise      Tateno; Rie      Utoh

Abstract

Conventionally, rodents, mostly mice and rats, have been utilized as animal models for studying drug metabolism and toxicity of new medicines. However, there have been two major problems inherent to these models. One is that there are species differences in major enzymes responsible for drug metabolisms and detoxification such as cytochrome P450 between rodents and humans, and the other is that human hepatitis viruses do not infect rodent livers, which hampers studies for anti-hepatitis virus drugs using these models. As an approach to overcome these intrinsic shortages, we devised a method to generate mice whose livers are mostly ( > 80%) repopulated with healthy human hepatocytes 7 years ago. Since then, these mice called simply chimeric mice or liver-humanized mice have been widely utilized among researchers in the areas for new drug developments, which, as a result, have proved that the chimeric mouse is a practical solution to solve the above two issues. The hitherto accumulated studies demonstrating the similarities of the chimeric mouse liver to the human crude liver are summarized and reviewed in the present article. In addition, there have been also studies that show us the presence of dissimilarities between them, such as human hepatocytes manifestation of hyperplasia in mouse liver and their steatotic alterations when the mice are maintained for > 50 days post-transplantation. These dissimilarities between them are also reviewed in details, considering that the information of the similarities and the dissimilarities is quite useful to researchers who utilize chimeric mice as a drug discovery tool for correctly evaluating the obtained results.

Keywords: Growth hormone, hepatic stellate cells, hepatitis viruses, in vivo drug testing, liver regeneration, liver steatosis, Micewith human liver, TGF- signaling, CHIMERIC MOUSE LIVER