Application of humanized mice to toxicology studies: properties of chimeric mice with humanized liver (PXB-mice) for hepatotoxicity

Abstract

Chimeric mice with humanized liver are considered a useful tool to predict drug pharmacokinetics and in vivo toxicity in humans. The PXB-mouse is one of such chimeric (humanized) mouse models with more than 70% of human hepatocytes in their liver, which can produce human albumin with human-type bile secretion and express human xenobiotic metabolizing enzymes. However, data are limited regarding the properties of such humanized mice in hepatotoxicity studies. This study aimed to explore the distinctive characteristics of chimeric PXB-mice with humanized liver that can influence susceptibility to hepatotoxicity. Morphologically, the PXB-mice have a diffuse hepatic macrovesicular and microvesicular steatosis in the transplanted human hepatocytes, which can be suppressed after human growth hormone treatment. The humanized liver of the PXB-mice has a metabolic zonation of glutamine synthetase, cytochrome P450 2E1, and argininosuccinate synthase 1, similar to normal liver in rodents and humans. The transplanted human hepatocytes in the PXB liver have a markedly decreased N-cadherin expression compared with normal human liver. Scanning electron microscopy revealed formation of septum-like structures encircling the transplanted human hepatocytes in the PXB liver, which consists of an accumulation of fibers in the space of Disse under transmission electron microscopy and is immunolabeled for laminin. Overall, the present report demonstrated the morphological and immunohistochemical characteristics of the PXB-mice with humanized liver along with some abnormalities in the cell adhesion of the transplanted human hepatocytes. These findings would be useful for hepatotoxicity studies using humanized animal models.