Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory Binu Shrestha1,2, J. Michael Reed2, Philip T. Starks2, Gretchen E. Kaufman3, Jared V. Goldstone4, Melody E. Roelke5, Stephen J. O’Brien6, Klaus-Peter Koepfli6, Laurence G. Frank7, Michael H. Court1* 1 Comparative and Molecular Pharmacogenomics Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, United States of America, 2 Department of Biology, Tufts University, Medford, Massachusetts, United States of America, 3 Department of Environmental and Population Health, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America, 4 Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America, 5 Laboratory of Genomic Diversity, SAIC-Frederick Incorporated, National Cancer Institute at Frederick, Frederick, Maryland, United States of America, 6 Laboratory of Genomic Diversity, National Cancer Institute at Frederick, Frederick, Maryland, United States of America, 7 Living with Lions Project (Kenya), Museum of Vertebrate Zoology, University of California, Berkeley, California, United States of America 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.
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