Physiological model of the stimulative effects of alcohol in low-to-moderate doses.

A physiological model of alcohol use is proposed, based on the observation that ethanol is a natural intracellular metabolite. It is suggested that ethanol synthesis is an intermediate step in the metabolic pathway of elimination of the excess of energy-releasing substrates from mitochondria and the cytosol when the cell does not require additional energy. The process is first of all important for elimination of acetyl-CoA from mitochondria. Ingested alcohol passes across plasma and mitochondrial membranes by diffusion and follows the endogenous ethanol pathway but in the reverse direction. This pathway is used when the cell needs additional energy. In that case, exogenous ethanol supplies the respiratory chain with electrons via NADH on the path of oxidation to acetaldehyde and then to acetate by alcohol and aldehyde dehydrogenases. After conversion to acetyl-CoA, it goes into the citrate cycle and is thus used for energy production entirely. If citrate cycle activity is decreased constitutionally, acetyl-CoA enters into citrate cycle too slowly and energy deficit arises, ethanol compensates for the energy deficit. Acetate then diffuses out of mitochondria. The less energy production in mitochondria, the more the cell is ready to accept alcohol as an energy source. Citrate cycle activity can be depressed as a result of single-nucleotide polymorphisms of genes controlling some enzymes involved in the cycle, which influences the alcohol requirement.