Challenge in evaluating human liver carcinogenicity of chemicals: Application of chimeric mice with human hepatocytes

<p>Phenobarbital (PB) produced liver tumors in rodents. Epidemiological studies have found no causal links between PB and human liver tumors. The constitutive androstane receptor (CAR)-mediated mode of action (MOA) for PB-induced rodent liver tumor formation has been established, and increased hepatocyte proliferation represents an essential preneoplastic key event in carcinogenesis. We have demonstrated that PB stimulates proliferation in cultured rat hepatocytes but not in cultured human hepatocytes. However, in the genetically humanized CAR and pregnane X receptor (PXR) mouse (hCAR/hPXR mouse, down-stream genes are still mouse), PB increased hepatocyte proliferation and tumor production in vivo. In contrast to hCAR/hPXR mouse, chimeric mice with human hepatocytes (both receptor and down-stream genes are human) revealed that PB did not increase human hepatocyte proliferation in vivo. As PB increased rat hepatocyte proliferation in the chimeric mouse with rat hepatocytes, lack of proliferation of human hepatocytes in the chimeric mouse is not due to any functional problem in the chimeric mouse liver environment. Global gene expression analysis demonstrated that down-stream genes of CAR/PXR are similar between the hCAR/hPXR mouse and CD-1 mouse. The findings strongly support that the MOA for CAR activator-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans, which is supported by the negative epidemiology. Based on our research, the chimeric mouse with human hepatocytes is reliable for human cancer risk assessment of test compounds.</p>