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-glucuronosy...
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ftpubmed:oai:pubmedcentral.nih.gov:3065456 2023-05-15T16:05:22+02:00 Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory Shrestha, Binu Reed, J. Michael Starks, Philip T. Kaufman, Gretchen E. Goldstone, Jared V. Roelke, Melody E. O'Brien, Stephen J. Koepfli, Klaus-Peter Frank, Laurence G. Court, Michael H. 2011-03-28 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065456 http://www.ncbi.nlm.nih.gov/pubmed/21464924 https://doi.org/10.1371/journal.pone.0018046 en eng Public Library of Science http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065456 http://www.ncbi.nlm.nih.gov/pubmed/21464924 http://dx.doi.org/10.1371/journal.pone.0018046 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. PDM CC0 Research Article Text 2011 ftpubmed https://doi.org/10.1371/journal.pone.0018046 2013-09-03T12:44:11Z 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. Text Elephant Seal PubMed Central (PMC) PLoS ONE 6 3 e18046 |
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Research Article Shrestha, Binu Reed, J. Michael Starks, Philip T. Kaufman, Gretchen E. Goldstone, Jared V. Roelke, Melody E. O'Brien, Stephen J. Koepfli, Klaus-Peter Frank, Laurence G. Court, Michael H. Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
topic_facet |
Research Article |
description |
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. |
format |
Text |
author |
Shrestha, Binu Reed, J. Michael Starks, Philip T. Kaufman, Gretchen E. Goldstone, Jared V. Roelke, Melody E. O'Brien, Stephen J. Koepfli, Klaus-Peter Frank, Laurence G. Court, Michael H. |
author_facet |
Shrestha, Binu Reed, J. Michael Starks, Philip T. Kaufman, Gretchen E. Goldstone, Jared V. Roelke, Melody E. O'Brien, Stephen J. Koepfli, Klaus-Peter Frank, Laurence G. Court, Michael H. |
author_sort |
Shrestha, Binu |
title |
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
title_short |
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
title_full |
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
title_fullStr |
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
title_full_unstemmed |
Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory |
title_sort |
evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory |
publisher |
Public Library of Science |
publishDate |
2011 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065456 http://www.ncbi.nlm.nih.gov/pubmed/21464924 https://doi.org/10.1371/journal.pone.0018046 |
genre |
Elephant Seal |
genre_facet |
Elephant Seal |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065456 http://www.ncbi.nlm.nih.gov/pubmed/21464924 http://dx.doi.org/10.1371/journal.pone.0018046 |
op_rights |
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. |
op_rightsnorm |
PDM CC0 |
op_doi |
https://doi.org/10.1371/journal.pone.0018046 |
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PLoS ONE |
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6 |
container_issue |
3 |
container_start_page |
e18046 |
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