Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.
Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, 9713 AV, Groningen, the Netherlands.
PLoS One. 2016 Mar 11;11(3):e0150064. doi: 10.1371/journal.pone.0150064. eCollection 2016.
The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.
肿瘤抑制因子视网膜母细胞瘤（Rb）和 p53 在肝脏疾病中经常失活，例如肝细胞癌（HCC）或乙型肝炎或丙型肝炎病毒感染。在这里，我们发现了 Rb 和 p53 在异生物代谢中的新作用，这是肝脏代谢治疗药物或毒素的关键功能。我们证明 Rb 和 p53 合作代谢异生物 3,5-二乙氧羰基-1,4-二氢吡啶（DDC）。DDC 主要由细胞色素 P450（Cyp）3a 酶代谢，导致血红素合成抑制和原卟啉积累，血红素途径的中间产物。原卟啉的积累会导致胆汁损伤和小管反应。我们表明，Rb 和 p53 的缺失导致 Cyp3a 表达减少，原卟啉积累减少，因此在喂食 DDC 的小鼠肝脏中小管反应减少 3 周。这些发现为 Rb 和 p53 的协同功能对 DDC 代谢至关重要提供了有力证据。由于 Rb 和 p53 功能在肝脏疾病中经常失活，我们的结果表明，肝脏患者可能会改变去除毒素或适当代谢治疗药物的能力。引人注目的是，对氧化应激诱导剂 DCC 的减少胆管损伤伴随着 Rb 和 p53 缺陷肝脏中肝细胞损伤和 HCC 的形成增加。肝细胞损伤的增加可能与原卟啉积累的减少有关，因为原卟啉因其抗氧化活性而广为人知。此外，我们的结果表明，Rb 和 p53 不仅在对致癌损伤的反应中作为肿瘤抑制因子起作用，而且在对非致癌损伤如 DDC 的反应中也起作用。
