Impact of ethanol and acetaldehyde on DNA and cell viability of cultured neurones.
Ethanol consumption has long been associated with brain damage. However, the mechanism underlying this deleterious effect remains unclear. Among different hypotheses, acetaldehyde is regarded by certain authors as playing a major role in the expression of ethanol toxicity, but there are still some uncertainties about the exact nature of its implication. We therefore tried to characterize the profile of the alterations of neuronal viability and DNA integrity obtained after either a direct exposure to ethanol or to acetaldehyde. Ethanol at concentrations within the range of blood alcohol levels in intoxicated humans (< or = 100 mmol/L) induced DNA alterations without any apparent effect on cell viability. Acetaldehyde (< or = 1000 micromol/L) can also induce DNA alterations but with a different profile of the DNA cellular alterations. The comparison between the distributions of the comet tail DNA indicated that ethanol induced strong breaks (tail DNA > or = 60 a.u.) generation whereas acetaldehyde rather induced lower breaks (20 < or = tail DNA < or = 50 a.u.) formation but affecting a greater number of neurones. Acetaldehyde had thus a different genotoxic potential which may suggest a different mode of action or a different cellular target. Furthermore, when a single 100 mmol/L ethanol exposure did not lead to any loss of cell viability, the addition of an inhibitor of aldehyde dehydrogenase was followed by a significant loss in viability. In contrast, the inhibition of catalase, which suppresses acetaldehyde synthesis, led to no reduced viability in the same exposure conditions. ROS also reduced viability, but this was observed only after both cytochrome P450 stimulation and catalase inhibition. These combined results could suggest that acetaldehyde may play a significant role in the expression of ethanol toxicity in brain.
Lamarche
F
F
Laboratoire Oligo-éléments et Résistance au Stress Oxydant induit par les Xénobiotiques (ORSOX, UMR-E UJF/CEA), Faculté de Médecine de Grenoble, Domaine de la Merci, La Tronche, France.
Gonthier
B
B
Signorini
N
N
Eysseric
H
H
Barret
L
L
D000079:Acetaldehyde / Q000494:pharmacology*; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D000431:Ethanol / Q000494:pharmacology*; D008751:Methylene Blue / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000431:Ethanol; D004247:DNA; D000079:Acetaldehyde; D008751:Methylene Blue; D010634:Phenobarbital; D000640:Amitrole