Department of Gastroenterology, St. Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
J Gastroenterol Hepatol. 2009 Jun;24(6):1038-44. doi: 10.1111/j.1440-1746.2009.05800.x.
It has been hypothesised, mainly from studies with animal models of liver disease, that the transport of substrates for metabolic enzymes and their subsequent metabolism and elimination in hepatic bile or blood is co-ordinated, but there is little information on this process in diseased human liver.
In this study we have measured by reverse transcription polymerase chain reaction (RT-PCR) major genes involved in drug metabolism from UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B4) and cytochrome P450 (CYP) families (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), transport (OATP-C, MRP2, MRP3, and MDR1) and major transcription factors (PXR, CAR, HNF1alpha, HNF4alpha, RXR, and AHR) involved in their regulation. Liver biopsy tissue from patients with viral hepatitis was scored for inflammation and fibrosis by the METAVIR system, and separated into groups with mild (A0-1; F0-1, n = 20) or severe (A2-3; F3-4, n = 19) liver disease. Correlation analysis (Spearman rank-test, P < 0.05) was used to identify metabolic enzymes and transporters which shared significant correlation with transcription factors.
Our results show an extensive correlation between transcription factors, transporters, and metabolic enzymes. An unexpected finding was that this was substantially greater in the severely diseased liver. Cross-talk between transcription factors was markedly increased in tissue from patients with severe liver disease, particularly between CAR, HNF4alpha, and PXR.
Our results support the hypothesis of co-ordinate regulation of metabolic enzymes and transporters in diseased human liver, as part of a widespread co-ordinated process under the control of nuclear receptor transcription factors.
主要基于肝脏疾病的动物模型研究提出了这样一种假说，即代谢酶的底物的转运及其随后在肝胆汁或血液中的代谢和消除是协调的，但关于患病人类肝脏中这一过程的信息很少。
在这项研究中，我们通过逆转录聚合酶链反应（RT-PCR）测量了涉及药物代谢的主要基因，这些基因来自 UDP-葡糖醛酸基转移酶（UGT1A1、UGT1A6、UGT1A9 和 UGT2B4）和细胞色素 P450（CYP）家族（CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1 和 CYP3A4）、转运（OATP-C、MRP2、MRP3 和 MDR1）以及调节它们的主要转录因子（PXR、CAR、HNF1alpha、HNF4alpha、RXR 和 AHR）。通过 METAVIR 系统对病毒性肝炎患者的肝活检组织进行炎症和纤维化评分，并将其分为轻度（A0-1；F0-1，n=20）或重度（A2-3；F3-4，n=19）肝病组。使用相关分析（Spearman 秩检验，P<0.05）来识别与转录因子具有显著相关性的代谢酶和转运体。
我们的结果显示转录因子、转运体和代谢酶之间存在广泛的相关性。一个意外的发现是，在严重患病的肝脏中，这种相关性要大得多。在严重肝病患者的组织中，转录因子之间的串扰明显增加，特别是在 CAR、HNF4alpha 和 PXR 之间。
我们的结果支持了患病人类肝脏中代谢酶和转运体协调调节的假说，这是核受体转录因子广泛协调过程的一部分。
