Abstract

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.

Highlights

  • Between- and within- species differences in the capacity to metabolize and eliminate drugs and other xenobiotics from the body are typically substantial, complicating the effective use of drugs, as well as minimizing the ability to predict the adverse consequences of environmental pollutants

  • To the best of our knowledge, this is the first study to identify the phylogenetic origin of a major drug metabolism deficiency during the evolution of a mammalian species

  • Our results indicate that complete loss of UGT1A6 mediated glucuronosyltransferase activity occurred via pseudogene fixation following divergence of the Felidae from all other feliform families approximately 37 million years ago (MYA), and prior to the initial divergence of the extant felid lineages 11 MYA

Read more

Summary

Introduction

Between- and within- species differences in the capacity to metabolize and eliminate drugs and other xenobiotics from the body are typically substantial, complicating the effective use of drugs, as well as minimizing the ability to predict the adverse consequences of environmental pollutants. Perhaps the best known example of a species defect of drug metabolism is the inability of domestic cats to metabolize drugs and structurally related phenolic compounds by glucuronidation [2,3,4,5,6,7]. Slow glucuronidation of acetaminophen [7] and acetylsalicylic acid (aspirin) [6] account for the slow clearance and exquisite sensitivity of cats to the adverse effects of these drugs compared with dogs and most other mammalian species

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call