One ADH isoenzyme that has been the focus of research on how dietary factors shape metabolic pathways due to its high expression in the upper gastrointestinal tissue is the ADH class IV, also known as ADH4 (21, 22). A recent genetic study spanning more than 171 species and across 7 mammalian orders found little evidence that sugar-rich diets, such as floral nectar and ripe fruit, drove mutations in the ADH7 gene (coding for the ADH4 isozyme) that favored ethanol metabolism (12). The only notable trend was observed in frugivorous and nectarivorous bats (12). Even though ADH4 likely evolved to oxidize non-ethanol endogenous substrates, such as retinol (19), there was a significant evolutionary mutation in this gene in most hominids approximately 10 million years ago. This mutation resulted in a 40-fold increase in the capacity to metabolize ethanol (23) and coincided with when great apes shifted to terrestrial habitats, enabling them to better tolerate ethanol found in fermenting fruit on the forest floor. Carn et al. (24) hypothesized that while this metabolic adaptation may have led to the accumulation of calories and fat from fructose metabolism, it may now increase the risk of excessive consumption and alcohol-related harm.
