Research Summary: Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory


The domestic cat (Felis catus) shows remarkable sensitivity to
the adverse effects of phenolic drugs, including acetaminophen and aspirin, as
well as structurally-related toxicants found in the diet and environment. This
idiosyncrasy results from pseudogenization of the gene encoding
UDP-glucuronosyltransferase (UGT) 1A6, the major species-conserved phenol
detoxification enzyme. Here, we established the phylogenetic timing of
disruptive UGT1A6 mutations and explored the hypothesis that
gene inactivation in cats was enabled by minimal exposure to plant-derived
toxicants. Fixation of the UGT1A6 pseudogene was estimated to
have occurred between 35 and 11 million years ago with all extant Felidae having
dysfunctional UGT1A6. Out of 22 additional taxa sampled,
representative of most Carnivora families, only brown hyena (Parahyaena
) and northern elephant seal (Mirounga
) showed inactivating UGT1A6
mutations. A comprehensive literature review of the natural diet of the sampled
taxa indicated that all species with defective UGT1A6 were
hypercarnivores (>70% dietary animal matter). Furthermore those
species with UGT1A6 defects showed evidence for reduced amino
acid constraint (increased dN/dS ratios approaching the neutral
selection value of 1.0) as compared with species with intact
UGT1A6. In contrast, there was no evidence for reduced
amino acid constraint for these same species within UGT1A1, the
gene encoding the enzyme responsible for detoxification of endogenously
generated bilirubin. Our results provide the first evidence suggesting that diet
may have played a permissive role in the devolution of a mammalian drug
metabolizing enzyme. Further work is needed to establish whether these
preliminary findings can be generalized to all Carnivora.


Publisher: Public Library of Science

Date Published: 28-March-2011

Author(s): Shrestha B., Reed J., Starks P., Kaufman G., Goldstone J., Roelke M., O’Brien S., Koepfli K., Frank L., Court M.


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