Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

Rao, P.S.S.; Midde, Narasimha M.; Miller, Duane D.; Chauhan, Subhash C.; Kumar, Anil; Kumar, Santosh

doi:10.2174/1389200216666150812123554

Cited by 80 publications

(71 citation statements)

References 171 publications

(180 reference statements)

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“…An early step in furan toxicity is uncoupling of hepatic oxidative phosphorylation, evidenced through lower ATP levels in rat hepatocytes and impaired respiration which preceded cell death in culture 81 . These effects can be ameliorated by administration of garlic oil 82 , which contains diallyl sulfide components that irreversibly inhibit CYP2E1 83 .…”

Section: Exogenous Substrates Of Cyp2e1 That Damage Mitochondriamentioning

confidence: 99%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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Cytochrome P450 2E1 (CYP2E1) metabolizes an extensive array of pollutants, drugs, and other small molecules, often resulting in bioactivation to reactive metabolites. Therefore, it is unsurprising that it has been the subject of decades of research publications and reviews. However, while CYP2E1 has historically been studied in the endoplasmic reticulum (erCYP2E1), active CYP2E1 is also present in mitochondria (mtCYP2E1). Relatively few studies have specifically focused on mtCYP2E1, but there is growing interest in this form of the enzyme as a driver in toxicological mechanisms given its activity and location. Many previous studies have linked total CYP2E1 to conditions that involve mitochondrial dysfunction (fasting, diabetes, non-alcoholic steatohepatitis, and obesity). Furthermore, a large number of reactive metabolites that are formed by CYP2E1 through metabolism of drugs and pollutants have been demonstrated to cause mitochondrial dysfunction. Finally, there appears to be significant inter-individual variability in targeting to the mitochondria, which could constitute a source of variability in individual response to exposures. This review discusses those outcomes, the biochemical properties and toxicological consequences of mtCYP2E1, and highlights important knowledge gaps and future directions. Overall, we feel that this exciting area of research is rich with new and important questions about the relationship between mtCYP2E1, mitochondrial dysfunction, and pathology.

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Section: Exogenous Substrates Of Cyp2e1 That Damage Mitochondriamentioning

confidence: 99%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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“…Furthermore, we chose compounds with smaller side chain (AES and AMS), which is likely to improve the binding affinity as well (Rao et al. ). Low molecular monocyclic aromatic compounds are also a viable option as the binding site of CYP2E1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DAS has been used most frequently in the prevention against toxicities induced by xenobiotics such as alcohol and acetaminophen by selectively inhibiting cytochrome P450 2E1 (CYP2E1) (Rao et al. ). CYP2E1 is involved in the metabolism of more than 85 xenobiotics (Trafalis et al.…”

Section: Introductionmentioning

confidence: 99%

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

Rahman

Midde

et al. 2017

Pharmacology Res & Perspec

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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.

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“…These include glucosinolates (Fuentes et al, 2015), curcuminoid (Prasad et al, 2014), organic sulfur compounds from garlic oil such as diallyl sulfide (Rao et al, 2015). All of these naturally occurring phytochemicals have been extended as nutriceuticals.…”

Section: Stilbene Compound-produced Changes In P450s Alas1 Transpormentioning

confidence: 99%

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

2016

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-A wide variety of drugs and chemicals have been shown to produce induction and inhibition of heme-metabolizing enzymes, and of drug-metabolizing enzymes, including cytochrome P450s (P450s, CYPs), which consist of many molecular species with lower substrate specificity. Such chemically induced enzyme alterations are coordinately or reciprocally regulated through the same and/or different signal transductions. From the toxicological point of view, these enzymatic changes sometimes exacerbate inherited diseases, such as precipitation of porphyrogenic attacks, although the induction of these enzymes is dependent on the animal species in response to the differences in the stimuli of the liver, where they are also metabolized by P450s. Since P450s are hemoproteins, their induction and/or inhibition by chemical compounds could be coordinately accompanied by heme synthesis and/or inhibition. This review will take a retrospective view of research works carried out in our department and current findings on chemical-induced changes in hepatic heme metabolism in many places, together with current knowledge. Specifically, current beneficial aspects of induction of heme oxygenase-1, a rate-limiting heme degradation enzyme, and its relation to reciprocal and coordinated changes in P450s, with special reference to CYP2A5, in the liver are discussed. Mechanistic studies are also summarized in relation to current understanding on these aspects. Emphasis is also paid to an example of a single chemical compound that could cause various changes by mediating multiple signal transduction systems. Current toxicological studies have been developing by utilizing a sophisticated "omics" technology and survey integrated changes in the tissues produced by the administration of a chemical, even in time-and dose-dependent manners. Toxicological studies are generally carried out step by step to determine and elucidate mechanisms produced by drugs and chemicals. Such approaches are correct; however, current "omics" technology can clarify overall changes occurring in the cells and tissues after treating animals with drugs and chemicals, integrate them and discuss the results. In the present review, we will discuss chemical-induced similar changes of heme synthesis and degradation, and of P450s and finally convergence to similar or different directions.

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Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

Cited by 80 publications

References 171 publications

Toxicological implications of mitochondrial localization of CYP2E1

Toxicological implications of mitochondrial localization of CYP2E1

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

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

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