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 gro wth. To date, it has been difficult to dissociate the primary effects of ethanol from the effects of ethanol metabolism, generation of aceta ldehyde, and reducing equivalents. We have previously described the de velopment of a Chinese hamster ovary cell line, A-10, which expresses a transfected murine-liver alcohol dehydrogenase. Cultures of these ce lls accumulate acetaldehyde due to the low level of aldehyde dehydroge nase. 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 w ith the A-10 cell on the rates of [H-3]thymidine incorporation and flo w cytometry of asynchronous cultures indicated that acetaldehyde did n ot lead to arrest of the cell cycle in the G(1) phase as has been foun d in other models of ethanol exposure. Rather, we observed a generaliz ed delay in cell cycle progression. However, the slower cell cycle did not account exclusively for the stower rates of cell accumulation. Ch ronic exposure to acetaldehyde also increased the rate of cell death. The increased rate of cell death was both cumulative and dose-dependen t. The dead cells accumulated in the medium and were apoptotic. Apopto sis was confirmed using morphological criteria and quantitation of DNA fragmentation. These data lend additional support to the idea that ch ronic acetaldehyde exposure can affect the mechanisms that regulate ce ll division and the apoptotic program.