The molecular mechanisms of diallyl disulfide and diallyl sulfide induced hepatocyte cytotoxicity.
Diallyl disulfide (DADS) and diallyl sulfide (DAS) are the major metabolites found in garlic oil and have been reported to lower cholesterol and prevent cancer. The molecular cytotoxic mechanisms of DADS and DAS have not been determined. The cytotoxic effectiveness of hydrogen versus allyl sulfides towards hepatocytes was found to be as follows: NaHS>DADS>DAS. Hepatocyte mitochondrial membrane potential was decreased and reactive oxygen species (ROS) and TBARS formation was increased by all three allyl sulfides. (1) DADS induced cytotoxicity was prevented by the H(2)S scavenger hydroxocobalamin, which also prevented cytochrome oxidase dependent mitochondrial respiration suggesting that H(2)S inhibition of cytochrome oxidase contributed to DADS hepatocyte cytotoxicity. (2) DAS cytotoxicity on the other hand was prevented by hydralazine, an acrolein trap. Hydralazine also prevented DAS induced GSH depletion, decreased mitochondrial membrane potential and increased ROS and TBARS formation. Chloral hydrate, the aldehyde dehydrogenase 2 inhibitor, however had the opposite effects, which could suggest that acrolein contributed to DAS hepatocyte cytotoxicity.
Graduate Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
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Truong
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Hindmarsh
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O'Brien
D000498:Allyl Compounds / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D002470:Cell Survival; D002478:Cells, Cultured; D004220:Disulfides / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D013440:Sulfides / Q000633:toxicity*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; D017382:Reactive Oxygen Species; D013440:Sulfides; D017392:Thiobarbituric Acid Reactive Substances; C028009:diallyl disulfide; C038491:allyl sulfide