Kinetic characterizations of diallyl sulfide analogs for their novel role as CYP2E1 enzyme inhibitors.

Abstract

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 IC50, K i, 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 i values (3.1 and 4.4 μmol/L, respectively, vs. 6.3 μmol/L for DAS) and IC50 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.