Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory

Binu Shrestha; J Michael Reed; Philip T Starks; Gretchen E Kaufman; Jared V Goldstone; Melody E Roelke; Stephen J O'Brien; Klaus-Peter Koepfli; Laurence G Frank; Michael H Court

doi:10.1371/journal.pone.0018046

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Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory

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Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory

Binu Shrestha, J Michael Reed, Philip T Starks, Gretchen E Kaufman, Jared V Goldstone, Melody E Roelke, Stephen J O'Brien, Klaus-Peter Koepfli, Laurence G Frank and Michael H Court

PloS one, Vol.6(3), pp.e18046-e18046

03/28/2011

DOI: https://doi.org/10.1371/journal.pone.0018046

Handle:

https://hdl.handle.net/2376/107932

PMCID: PMC3065456

PMID: 21464924

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Abstract

Amino Acid Sequence

Species Specificity

Codon, Terminator - genetics

Cats - genetics

Molecular Sequence Data

Feeding Behavior

Phylogeny

Open Reading Frames - genetics

Seals, Earless - genetics

Hyaenidae - genetics

Glucuronosyltransferase - genetics

Pseudogenes - genetics

Animals

Glucuronosyltransferase - chemistry

Diet

Time Factors

Base Sequence

Inactivation, Metabolic - genetics

Frameshift Mutation - genetics

Evolution, Molecular

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.

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Title: Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory
Creators: Binu Shrestha - Comparative and Molecular Pharmacogenomics Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
J Michael Reed
Philip T Starks
Gretchen E Kaufman
Jared V Goldstone
Melody E Roelke
Stephen J O'Brien
Klaus-Peter Koepfli
Laurence G Frank
Michael H Court
Publication Details: PloS one, Vol.6(3), pp.e18046-e18046
Academic Unit: Veterinary Clinical Sciences, Department of; Paul G. Allen School for Global Animal Health
Publisher: United States
Grant note: N01-CO-12400 / NCI NIH HHS Intramural NIH HHS R01GM061834 / NIGMS NIH HHS N01CO12400 / NCI NIH HHS R01 GM061834 / NIGMS NIH HHS
Identifiers: 99900547040601842
Language: English
Resource Type: Journal article