Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Drug Metab Dispos. 2022 Jul;50(7):1019-1026. doi: 10.1124/dmd.121.000481. Epub 2022 Feb 19.
Pregnane X receptor (PXR) and constitutively active receptor/constitutive androstane receptor (CAR) are xenobiotic-responsible transcription 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 precise mechanism for phenobarbital/CAR-mediated liver tumor formation remains to be established, intracellular pathways, including the Hippo pathway/Yes-associated protein-TEA-domain family members system and -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 proliferation 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-mesenchymal 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 mechanisms and species differences. SIGNIFICANCE STATEMENT: Pregnane X receptor and constitutively active receptor/constitutive androstane receptor have very similar functions in the gene regulation associated with xenobiotic disposition, as suggested by their identification as xenosensors for enzyme induction. In contrast, recent reports clearly suggest that these receptors play distinct roles in the control of hepatocyte proliferation and liver cancer development. Understanding these differences at the molecular level may help us evaluate the human safety of chemical compounds and develop novel drugs targeting liver cancers.
pregnane X 受体（PXR）和组成型激活受体/组成型雄烷受体（CAR）是属于同一核受体基因亚家族的外源性物质反应性转录因子，在肝脏中高度表达。这些受体被各种化学物质激活，在许多肝脏功能中发挥关键作用，包括外源性物质代谢和处置。苯巴比妥，一种酶诱导剂和肝癌促进剂，激活啮齿动物和人类的 CAR，但仅在啮齿动物中引起肝癌。尽管苯巴比妥/CAR 介导的肝癌形成的确切机制仍有待确定，但包括 Hippo 途径/Yes 相关蛋白-TEA 结构域家族成员系统和 -连环蛋白信号在内的细胞内途径似乎参与其中。与 CAR 相反，我们小组的先前发现表明，PXR 激活不会促进肝细胞增殖，但会增强各种刺激引起的增殖。此外，令人惊讶的是，PXR 通过靶向炎症细胞因子信号、血管生成和上皮-间充质转化，可能对啮齿动物和人类具有抗肿瘤作用。在这篇综述中，我们总结了目前关于 PXR 和 CAR 与肝细胞增殖和肝癌发生的关联及其分子机制和种间差异的知识。意义陈述：PXR 和 CAR 在与外源性物质处置相关的基因调控中具有非常相似的功能，这表明它们是酶诱导的外源性物质传感器。相比之下，最近的报告清楚地表明，这些受体在外源性物质处置相关的基因调控中具有非常相似的功能，这些受体在控制肝细胞增殖和肝癌发展方面发挥着不同的作用。在分子水平上理解这些差异可能有助于我们评估化学化合物的人体安全性并开发针对肝癌的新型药物。
