Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, 38163.
Pharmacol Res Perspect. 2017 Oct;5(5). doi: 10.1002/prp2.362.
Diallyl sulfide (DAS), a selective inhibitor of CYP2E1, has shown protective effects against alcohol- and acetaminophen-induced hepatotoxicity in many studies. However, DAS is also a CYP2E1 substrate that on metabolism produces toxic metabolites and causes cytotoxicity. The objective of this study was to find a potent DAS analog as a CYP2E1 inhibitor and has the characteristic of producing less toxic metabolites. We selected seven commercially available compounds that are similar to DAS (DAS analogs). First, we performed ligand-CYP2E1 docking study to determine the binding mode and binding energy. The analysis suggested a relative potential for these DAS analogs as CYP2E1 inhibitor. We then performed a comprehensive inhibition kinetics of DAS analogs and determined the relative IC , K , and types of inhibition compared to that of DAS. The results showed that compared to DAS, diallyl ether and allyl methyl sulfide have lower K values (3.1 and 4.4 μmol/L, respectively, vs. 6.3 μmol/L for DAS) and IC values (6.3 and 11.4 μmol/L, respectively, vs. 17.3 μmol/L for DAS). However, allyl methyl sulfide and thiophene showed similar inhibitory capacities to that of DAS, and four other DAS analogs showed lower potency than DAS. In conclusion, we have found relatively more potent inhibitors of CYP2E1, which have lower toxicity than DAS. These compounds can replace DAS not only as a tool for in vitro and in vivo studies that involve CYP2E1 inhibition, but also can lead the way for their use in preventing CYP2E1-mediated hepatic toxicity of alcohol and acetaminophen.
二烯丙基二硫（DAS）是 CYP2E1 的选择性抑制剂，在许多研究中显示出对酒精和对乙酰氨基酚引起的肝毒性的保护作用。然而，DAS 也是 CYP2E1 的底物，在代谢过程中会产生有毒代谢物并引起细胞毒性。本研究的目的是寻找一种有效的 DAS 类似物作为 CYP2E1 抑制剂，并且具有产生较少毒性代谢物的特征。我们选择了七种与 DAS 相似的市售化合物（DAS 类似物）。首先，我们进行了配体-CYP2E1 对接研究，以确定结合模式和结合能。分析表明，这些 DAS 类似物具有相对的 CYP2E1 抑制潜力。然后，我们对 DAS 类似物进行了全面的抑制动力学研究，并确定了与 DAS 相比的相对 IC50、K 值和抑制类型。结果表明，与 DAS 相比，二烯丙基醚和烯丙基甲基硫醚的 K 值（分别为 3.1 和 4.4 μmol/L，而 DAS 为 6.3 μmol/L）和 IC 值（分别为 6.3 和 11.4 μmol/L，而 DAS 为 17.3 μmol/L）较低。然而，烯丙基甲基硫醚和噻吩与 DAS 的抑制能力相似，而其他四种 DAS 类似物的活性低于 DAS。总之，我们发现了相对更有效的 CYP2E1 抑制剂，其毒性低于 DAS。这些化合物不仅可以替代 DAS 作为涉及 CYP2E1 抑制的体外和体内研究的工具，而且还可以为预防 CYP2E1 介导的酒精和对乙酰氨基酚肝毒性开辟道路。
