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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 , Ki , and types of inhibition compared to that of DAS. The results showed that compared to DAS, diallyl ether and allyl methyl sulfide have lower Ki values (3.1 and 4.4 ?mol/L, respectively, vs. 6.3 ?mol/L for DAS) and IC50 values (6.3 and 11.4 ?mol/L, respectively, vs. 17.3 ?mol/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.

SUBMITTER: Rahman MA

PROVIDER: S-EPMC5625166 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Rahman Mohammad A MA Midde Narasimha M NM Wu Xiaoxin X Li Wei W Kumar Santosh S

Pharmacology research & perspectives 20171001 5

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 ana ...[more]

PMID: 28971616

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Project description:Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnTR141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS‑induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria‑dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin‑converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.

Dataset Information

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

Publications

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

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