Human hepatocytes are protected from ethanol-induced cytotoxicity by DADS via CYP2E1 inhibition.
We investigated the protective effects of diallyl disulfide (DADS), a potent inhibitor of cytochrome P450 2E1 (CYP2E1), on ethanol-induced toxicity in human hepatocytes. We found a clear dose-dependent response between ethanol and CYP2E1 activity. The ethanol-dependent CYP2E1 enzyme activity and protein expression, lactate dehydrogenase and aspartate transaminase release, malondialdehyde formation and caspase-3 activity decreased dramatically in the presence of DADS. Furthermore, DADS increased the hepatocellular glutathione (GSH) content and prevented the ethanol-dependent cellular GSH depletion. Our data show that DADS reduces ethanol-induced toxicity in human hepatocytes by reducing CYP2E1 activity and/or stabilizing the cellular GSH content, which might be of therapeutic interest.
Shimada
Masashi
M
Department of General-, Visceral-, and Transplantation Surgery, Charite, Campus Virchow, Humboldt-University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Liu
Liegang
L
Nussler
Natascha
N
Jonas
Sven
S
Langrehr
Jan M
JM
Ogawa
Toshihisa
T
Kaminishi
Michio
M
Neuhaus
Peter
P
Nussler
Andreas K
AK
D000498:Allyl Compounds / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D013440:Sulfides; D000431:Ethanol; D008315:Malondialdehyde; C038491:allyl sulfide; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione