In vivo modeling of human liver for pharmacological study using humanized mouse.

The liver occupies a central place in the treatment of the substances taken into the body. If we could devise an in vivo or in vitro model that perfectly mimics the naturally-created human (h) liver, the work required for making effective and safe medicines would become easier and could be undertaken more cost effectively than it is currently. Considering the advantages of in vivo modeling over in vitro modeling under the current technological state of life sciences research, we have created an experimentally workable in vivo h-liver model, a liver-humanized mouse, in which host hepatocytes are largely replaced with healthy normal h-hepatocytes. Xenogenic h-hepatocytes are capable of constructing a histologically normal liver by collaborating with mouse-nonparenchymal cells in an elaborately organized manner. Considering its potential use for drug development, we have extensively characterized the mouse regarding the infectivity toward h-hepatitis viruses, activities of h-enzymes in Phase I and II of drug metabolisms, and h-hepatocyte-related drug transporters. These studies indicate that the humanized mouse liver mimics h-phenotypes at a level appropriate for pharmacological studies, and, thus, can be used not only for developing new medicines, but also for examining biological and pathological mechanisms in the h-liver.