Department of Toxicology, P.O. Box 616, 6200 MD, Maastricht, Maastricht University, The Netherlands.
Department of Toxicology, P.O. Box 616, 6200 MD, Maastricht, Maastricht University, The Netherlands.
Chem Biol Interact. 2015 Dec 5;242:139-44. doi: 10.1016/j.cbi.2015.09.024. Epub 2015 Sep 30.
Cytochrome P450 2E1 (CYP2E1) expression and activity in the liver is associated with the degree of liver damage in patients with alcoholic steatohepatitis (ASH) as well as non-alcoholic steatohepatitis (NASH). CYP2E1 is known to generate reactive oxygen species, which leads to oxidative stress, one of the hallmarks of both diseases. Apart from ROS, toxic metabolites can be formed by CYP2E1 metabolism, further potentiating liver injury. Therefore, CYP2E1 is implicated in the pathogenesis of ASH and NASH. The aim of this study was to determine the chemical characteristics of compounds that are important to inhibit CYP2E1. To this end, structurally related analogs that differed in their lipophilic, steric and electronic properties were tested. In addition, homologues series of aliphatic primary alcohols, secondary alcohols, aldehydes, ketones and carboxylic acids were tested. It was found that inhibition of the CYP2E1 activity is primarily governed by lipophilicity. The optimal log D7.4 (octanol/water distribution coefficient at pH 7.4) value for inhibition of CYP2E1 was approximately 2.4. In the carboxylic acids series the interaction of the carboxylate group with polar residues lining the CYP2E1 active site also has to be considered. This study sketches the basic prerequisites in the search for inhibitors of CYP2E1, which would strengthen our therapeutic armamentarium against CYP2E1 associated diseases, such as ASH and NASH.
细胞色素 P450 2E1（CYP2E1）在肝脏中的表达和活性与酒精性脂肪性肝炎（ASH）和非酒精性脂肪性肝炎（NASH）患者的肝损伤程度有关。众所周知，CYP2E1 会产生活性氧，从而导致氧化应激，这是这两种疾病的特征之一。除了 ROS 之外，CYP2E1 代谢还可以形成有毒代谢物，进一步加剧肝损伤。因此，CYP2E1 与 ASH 和 NASH 的发病机制有关。本研究旨在确定对抑制 CYP2E1 很重要的化合物的化学特性。为此，测试了在亲脂性、立体和电子性质上有所不同的结构相关类似物。此外，还测试了脂肪族伯醇、仲醇、醛、酮和羧酸的同系物系列。结果发现，CYP2E1 活性的抑制主要受亲脂性控制。抑制 CYP2E1 的最佳 log D7.4（pH 7.4 时的辛醇/水分配系数）值约为 2.4。在羧酸系列中，还必须考虑羧酸基团与排列在 CYP2E1 活性部位的极性残基的相互作用。这项研究概述了寻找 CYP2E1 抑制剂的基本前提条件，这将增强我们对抗 CYP2E1 相关疾病（如 ASH 和 NASH）的治疗手段。
