Michael Court

Michael Court, associate professor of Molecular Physiology & Pharmacology, published Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory in PLoS One, with Tufts co-authors Binu Shrestha from the Tufts University School of Medicine, J Michael Reed and Philip T Starks from the Tufts School of Arts and Sciences, and Gretchen E Kaufman from the Tufts Cummings School of Veterinary Medicine. The abstract is below –

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.

Michael has answered some questions about open access.

Please tell us a little about the research that went into this article.
During my training as a veterinarian (over 30 years ago) I learned that domestic cats are unusually sensitive to the adverse effects of a number of phenolic drugs including aspirin and acetaminophen. However, there was no good explanation at that time as to why this happens either from a biological or an evolutionary perspective. Consequently I chose this as a topic for my PhD thesis work. I found that the gene encoding the enzyme responsible detoxifying aspirin and acetaminophen (UGT1A6) contained multiple (at least 5) different inactivating mutations in all the cats we studied. Given the number of mutations and the consistency of the findings between individual cats, we suspected that disruption of the gene was quite ancient, perhaps predating the divergence of the modern cat from other cat-like species (lions, tigers and so on). Furthermore, we wondered whether cats had lost the ability to make this enzyme because they have a diet strictly composed of animal matter (hypercarnivores) and have no need to detoxify phenolic compounds normally found in plant derived foods (the “use it or lose it” paradigm). This current paper describes the work of one of my graduate students (Binu Shrestha) that explored each of these hypotheses focusing mainly on the mammalian order Carnivora using DNA samples provided by researchers from around the world. Using advanced molecular genetic techniques Binu found that the disruption of the UGT1A6 gene had occurred initially in a common ancestor of all the modern cat-like (Felidae) species the approximately 11 to 35 million years ago. In addition, she identified 2 other species (brown hyena and northern elephant seal) with disrupting UGT1A6 mutations – although these mutations appeared to be quite recent and might not affect all their species. Most importantly, she found that all of the species she surveyed that were hypercarnivores (i.e. had greater than 70% animal matter in their diet) also had lower selection pressure on their UGT1A6 gene sequence. These findings (although preliminary since we didn’t study a huge number of species) imply that the natural diet of a particular species might be used to predict their sensitivity to the adverse effects of certain drugs – especially those similar in structure to plant derived intoxicants. The work also suggests that all of the Felidae species are likely to be sensitive to aspirin and acetaminophen (like the domestic cat) since they lack a functional UGT1A6 enzyme. This latter finding should be of benefit to zoo and wildlife veterinarians treating these species.

Why did you choose to publish in an open access journal?
I wanted to reach as broad an audience as possible – especially for veterinarians and researchers in resource poor regions that have limited access to the journals that normally publish my work.

How do you think open access will influence your field in the future?
I am starting to see more and more papers in my field being published in open access journals. The gap between page charges for traditional journals and the costs of open access publishing is narrowing making open access a viable option for authors especially for work that you want to have broad dissemination.