Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland.
Pharmacol Rep. 2012;64(4):927-39. doi: 10.1016/s1734-1140(12)70888-5.
Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end-stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis).
Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control.
Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up-regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line.
As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes.
药物代谢酶和药物转运体在肝脏中的表达主要受核受体系统调控。本研究旨在探讨核受体以及这些酶和转运体在各种病因（丙型肝炎病毒感染、酒精性肝病和原发性硬化性胆管炎）所致终末期肝病患者肝脏样本中的表达情况。
使用定量实时 PCR 测量来自终末期肝病患者手术标本和作为对照的非肿瘤性肝组织中的基因表达。
我们的研究证实，大多数 I 相酶在终末期肝病中表达受到抑制，并且与外源性物质代谢的主要调节剂 NR1I2 和 NR1I3 的减少相关。虽然 II 相酶的 mRNA 水平通常不变，但一些 ABC 转运体上调。表达水平增加最显著的是 ABCC4（MRP4）-在 mRNA 水平，和 CYP1B1-在 mRNA 和蛋白质水平。我们还证明，IL-6 可以独立于 CYP1A1 诱导 CYP1B1 的表达，在人肝癌细胞系中。
由于 CYP1B1 是将各种底物转化为致癌代谢物的酶，其在肝脏中的过度表达可能是增加肝病患者肝癌风险的因素之一。CYP1A1 和 CYP1B1 通常被称为 AHR 靶基因模型，但在疾病肝样本中 CYP1A1 下调。这表明这两个基因的调控存在差异。
