Simple SummaryOur study investigates a specific genetic loss and duplication in elephants by comparing genomic data from 12 different mammalian species. We created a synteny map and phylogenetic tree of the selected species, which suggested that elephant CYP1–4 genes have undergone independent duplication, particularly in the CYP2A, CYP2C, and CYP3A genes, a unique cluster found only in elephants. In contrast, CYP2E and CYP4A might have decayed to a state of genetic dysfunction (pseudogene). These results suggest the need for further investigations into elephant genomics to evaluate the species’ metabolic mechanisms.AbstractCytochrome P450 is an important enzyme that metabolizes a variety of chemicals, including exogenous substances, such as drugs and environmental chemicals, and endogenous substances, such as steroids, fatty acids, and cholesterol. Some CYPs show interspecific differences in terms of genetic variation. As little is known about the mechanisms of elephant metabolism, we carried out a comparative genomic and phylogenetic analysis of CYP in elephants. Our results suggest that elephant CYP genes have undergone independent duplication, particularly in the CYP2A, CYP2C, and CYP3A genes, a unique cluster specific to elephant species. However, while CYP2E and CYP4A were conserved in other Afrotheria taxa, their decay in elephants resulted in genetic dysfunction (pseudogene). These findings outline several remarkable characteristics of elephant CYP1–4 genes and provide new insights into elephant xenobiotic metabolism. Further functional investigations are necessary to characterize elephant CYP, including expression patterns and interactions with drugs and sensitivities to other chemicals.