Comparative genomics and transcriptome analysis reveal unique features of xenobiotic-metabolizing enzymes in elephants.

Elephants, the largest terrestrial mammals, have distinctive metabolic features that may explain their increased sensitivity to xenobiotics, including environmental pollutants and pharmaceuticals. While previous in silico studies have identified unique patterns in elephant cytochrome P450 (CYP), Phase I xenobiotic-metabolizing enzymes, much less is known about their Phase II enzyme systems. This study combines comparative genomic, phylogenetic, and transcriptomic analyses to thoroughly examine Phase I and Phase II xenobiotic-metabolizing enzymes in African (Loxodonta africana) and Asian elephants (Elephas maximus). Genomic analyses revealed extensive duplication of UGT2B isoforms, which encode important enzymes that conjugate plant secondary metabolites, in both species. Conversely, SULT1B1, involved in tyrosine and thyroid hormone metabolism, was missing in both elephant species, while SULT1D1, related to dopamine metabolism, was uniquely absent in Asian elephants. RNA-seq analysis of liver, kidney, and small intestine samples from two Asian elephants confirmed similar patterns, with high hepatic expression of UGT2B isoforms and complete absence of SULT1B and SULT1D. CYP expression also showed a distinctive profile, with major hepatic CYP families, CYP2A, 2C, 2D, and 3A being expressed, but CYP2E and CYP4A were absent. Taken together, these results highlight the unique Phase I/II metabolic profile of elephants and emphasize the importance of functional studies to determine how such species-specific enzymatic patterns influence xenobiotic susceptibility and pharmacological responses.