Ethanol - Carbon Tetrachloride Interactions in Mammalian Systems.

The objective of this work was to investigate the hepatotoxic and fetotoxic response to combined exposures of ethanol and CCl(,4), and to investigate the underlying biochemical interaction at the second oxidation step in alcohol metabolism catalyzed by aldehyde dehydrogenase (ALDH). In vitro studies suggested that CCl(,4), under conditions suitable for its metabolism, could significantly inhibit microsomal and mitochondrial ALDH. A similar inhibition was observed in vivo when animals were exposed to CCl(,4) or CCl(,4) preceded 18 hours earlier by ethanol. The observed loss in microsomal ALDH activity one hour after CCl(,4) treatment (a 37% decline in activity). Similarly, treated animals sacrificed 24 hours following CCl(,4) treatment were found to have a 52% decline in ALDH activity due to CCl(,4) alone, and a 75% decline in ALDH activity in ethanol + CCl(,4) treated animals. Since acetaldehyde and some aldehydic products of lipid peroxidation are metabolized by ALDH, our data would suggest that ALDH inhibition may be a major contributory mechanism for the observed ethanol potentiation of CCl(,4) hepatotoxicity. However, the failure to accumulate acetaldehyde suggested that this aldehyde was not responsible for the observed potentiation. In vitro and in vivo investigations into the effects of CCl(,4) on placental ALDH revealed that the placenta's capacity to metabolize aldehydes was essentially uncompromised following CCl(,4) exposure. Therefore, it was of interest to observe the combined effects of ethanol and CCl(,4) on the developing mouse fetus at a time when placental ALDH and fetal ALDH have not yet matured. A significant increase in resorption sites was observed in dams receiving ethanol + CCl(,4) compared to those dams receiving either agent alone. However, whether the observed additive fetotoxic response was due to maternally generated aldehydes, or to a combined anesthetic effect, will require further investigation.Ph.D.PharmacologyPublic healthUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/159760/1/8402304.pd