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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 brunnea ) and northern elephant seal ( Mirounga angustirostris ) 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.

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