Mechanisms of acetaldehyde-mediated growth inhibition: delayed cell cycle progression and induction of apoptosis.
Chronic ethanol exposure has been associated with pleiotropic effects on cellular function in vivo and in vitro, including inhibition of growth. To date, it has been difficult to dissociate the primary effects of ethanol from the effects of ethanol metabolism, generation of acetaldehyde, and reducing equivalents. We have previously described the development of a Chinese hamster ovary cell line, A-10, which expresses a transfected murine-liver alcohol dehydrogenase. Cultures of these cells accumulate acetaldehyde due to the low level of aldehyde dehydrogenase. One noticeable effect of chronic acetaldehyde exposure, but not ethanol exposure, is the inhibition of cell growth. This study focuses on the mechanisms that underlie this growth inhibition. Our studies with the A-10 cell on the rates of [3H]thymidine incorporation and flow cytometry of asynchronous cultures indicated that acetaldehyde did not lead to arrest of the cell cycle in the G1 phase as has been found in other models of ethanol exposure. Rather, we observed a generalized delay in cell cycle progression. However, the slower cell cycle did not account exclusively for the slower rates of cell accumulation. Chronic exposure to acetaldehyde also increased the rate of cell death. The increased rate of cell death was both cumulative and dose-dependent. The dead cells accumulated in the medium and were apoptotic. Apoptosis was confirmed using morphological criteria and quantitation of DNA fragmentation. These data lend additional support to the idea that chronic acetaldehyde exposure can affect the mechanisms that regulate cell division and the apoptotic program.
Zimmerman
B T
BT
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Crawford
G D
GD
Dahl
R
R
Simon
F R
FR
Mapoles
J E
JE
D000079:Acetaldehyde / Q000494:pharmacology*; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics; D002461:Cell Line, Transformed; D006224:Cricetinae; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008875:Middle Aged; D014162:Transfection
D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde