Elephant alcohol dehydrogenase and aldehyde dehydrogenase: Genomic, transcriptomic, and enzymatic analyses raise questions about anecdotal inebriation.

Anecdotal accounts of inebriated elephants are widespread across elephant-inhabited regions, yet the molecular and mechanistic basis underlying these observations remains incompletely understood. Alcohol metabolism in mammals is primarily mediated by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). We investigated elephant ADH and ALDH at the genomic, transcriptional, and enzymatic levels, comparing them with humans, hamsters, and rats. Elephant liver predominantly expressed three ADH1 genes, as in humans and hamsters that voluntarily consume ethanol, a feature otherwise reported mainly in primates. We measured hepatic ADH and cytosolic ALDH activities in elephants, despite challenges in sample collection. Elephant ADH exhibited high ethanol affinity, allowing enzymatic activity at low substrate concentrations, likely related to large body size. ADH catalytic efficiency was comparable to other species, and cytosolic ALDH showed relatively high efficiency. These results suggest that elephants are less likely to possess exceptionally low hepatic ethanol-metabolizing capacity, although the lack of data on mitochondrial ALDH2 activity should be taken into consideration. Elephants also exhibited unique features, including the absence of ADH4 gene expression, duplication of ALDH1A1, and pseudogenization of ALDH1B1, which appear to have arisen in association with diet and potential functional redundancy among paralogs. In addition to their ecological and evolutionary significance, these findings may contribute to the interpretation of drug metabolism and support evidence-based pharmacological management in elephants, given the role of ADH and ALDH in pharmaceutical metabolism. Together, this study provides a molecular and enzymatic basis for understanding ethanol metabolism in elephants.