Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
PLoS One. 2013 Apr 23;8(4):e61802. doi: 10.1371/journal.pone.0061802. Print 2013.
Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPARα activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPARα activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16α-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPARα is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics.
异源生物反应性核受体孕烷 X 受体 (PXR)、组成型激活/雄激素受体 (CAR) 和过氧化物酶体增殖物激活受体 α (PPARα) 在肝脏的代谢功能中发挥关键作用，如异源生物解毒和能量代谢。虽然 CAR 或 PPARα 的激活会在啮齿动物模型中诱导肝细胞增殖和肝癌发生，但 PXR 激活是否也具有这种作用尚不清楚。在本研究中，我们通过 1,4-双[2-(3,5-二氯吡啶氧基)]苯 (TCPOBOP) 和苯巴比妥或 PPARα 激活剂 Wy-14643 研究了 PXR 在异源生物诱导的肝细胞增殖中的作用，无论是否有 CAR 激活。正如预期的那样，用 TCPOBOP 或苯巴比妥处理会增加 Ki-67 阳性核的百分比以及肝脏中与细胞增殖相关基因的 mRNA 水平。另一方面，单独用 PXR 激动剂孕烯醇酮 16α-腈 (PCN) 处理没有显示出这种效果。令人惊讶的是，PCN 共同处理显著增强了野生型小鼠中 CAR 激活引起的肝细胞增殖，但在 PXR 缺陷型小鼠中没有。有趣的是，PXR 激活也增强了 Wy-14643 处理引起的肝细胞增殖。此外，PCN 处理增加了肝细胞的 RNA 含量，提示诱导 G0/G1 期过渡，并降低了细胞周期起始抑制剂 Cdkn1b 和 Rbl2 的 mRNA 水平。我们目前的发现表明，尽管 PXR 激活本身不会导致小鼠肝脏中的细胞增殖，但 CAR 或 PPARα 介导的异源生物诱导的肝细胞增殖会被 PXR 共同激活增强。因此，PXR 可能在暴露于异源生物时在肝细胞/肝脏增生中发挥新的独特作用。
