Special Section on Drug Metabolism and Regulation-Minireview

Pregnane X receptor (PXR) and constitutively active receptor/constitu-tive androstane receptor (CAR) are xenobiotic-responsible transcrip-tion factors belonging to the same nuclear receptor gene subfamily and highly expressed in the liver. These receptors are activated by a variety of chemicals and play pivotal roles in many liver functions, including xenobiotic metabolism and disposition. Phenobarbital, an enzyme inducer and liver tumor promoter, activates both rodent and human CAR but causes liver tumors only in rodents. Although the pre-cise mechanism for phenobarbital/CAR-mediated liver tumor forma-tion remains to be established, intracellular pathways, including the Hippo pathway/Yes-associated protein-TEA-domain family members system and b-catenin signaling, seem to be involved. In contrast to CAR, previous findings by our group suggest that PXR activation does not promote hepatocyte proliferation but it enhances the prolifer-ation induced by various stimuli. Moreover, and surprisingly, PXR may have antitumor effects in both rodents and humans by targeting inflammatory cytokine signals, angiogenesis and epithelial-mes-enchymal transition. In this review, we summarize the current knowledge on the associations of PXR and CAR with hepatocyte proliferation and liver tumorigenesis and their molecular mecha-nisms and species differences.