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.

Plasma exosomes exacerbate alcohol- and acetaminophen-induced toxicity via CYP2E1 pathway

“…In our laboratory, we have identified several analogs of diallyl sulfide (DAS) as more potent and relatively safer CYP2E1 inhibitors. Diallyl ether (DE) is one of the analogs with the best CYP2E1 inhibitory capacity and lowest toxicity profile 36,37 . We pretreated HepaRG cells with ALC and/or APAP and plasma exosomes with or without pre-treatment with DE.…”

The role of cytochrome P450 2E1 on ethanol-mediated oxidative stress and HIV replication in human monocyte-derived macrophages

“…4B, *p < 0.05 compared to control scramble siRNA, ##p < 0.001 compared to ethanol scramble siRNA). Furthermore, we treated U1 cells with a novel CYP2E1 inhibitor diethyl ether (DE), which has been identified by our group [31], to further examine the role of CYP2E1 in ethanol-enhanced HIV-1 replication. As expected, selective CYP2E1 inhibitor DE significantly decreased the level of HIV-1 replication (~25%) upon ethanol exposure (Fig.…”

In vitro evaluation of structural analogs of diallyl sulfide as novel CYP2E1 inhibitors for their protective effect against xenobiotic-induced toxicity and HIV replication

“…Hence, a low molecular weight cyclic compound (TP) is expected to work as a potent inhibitor but not as a substrate due to its cyclic structure. Our inhibition study showed that two analogs (DE and AMS) were stronger CYP2E1 inhibitors than DAS, TP had a similar inhibitory capacity to DAS, and the other analogs showed moderate CYP2E1 inhibition (Rahman et al, 2017). Despite the differences in the magnitude of their inhibition, we included all seven analogs for this in vitro toxicity and efficacy study.…”

“…We hypothesize that modification of the parent DAS structure would result in analogs with improved CYP2E1 inhibition capacity and reduced cytotoxicity. In our previous study, based on a computational ligand-docking analyses, we evaluated seven structural analogs (allyl methyl sulfide, allyl ethyl sulfide, diallyl ether, thiophene, 2-(prop-2-en-1-yloxy) ethan-1-amine, 5-hexen-1-amine, and 2-prop-2-enoxyacetamide) of DAS for their CYP2E1–inhibitory properties (Rahman et al, 2017). We found that two analogs (diallyl ether and allyl methyl sulfide) had greater CYP2E1 inhibitory capacity than DAS, while other analogs showed inhibitory capacity for CYP2E1 similar to DAS.…”