OMIA 001586-9685 : Deficient acetaminophen glucuronidation in Felis catus

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2000

Molecular basis: By cloning and sequencing a very likely candidate gene (based on the observation that "The domestic cat has a significantly lower capacity to glucuronidate planar phenolic xenobiotics compared with most other mammalian species"), Court and Greenblatt (2000) showed that all cats are homozygous for a mutated form of the UGT1A6 gene that encodes UDP-glucuronosyltransferase 1A6, and hence completely lack this most important phenol-detoxification enzyme. From comparative analyses, Shrestha et al. (2011) concluded that the mutated form of the gene was fixed between 35 and 11 million years ago, resulting in all Felidae being homozygous for the mutated gene and hence the lack of the enzyme. As Shrestha et al. (2011) note, this accounts for felid's "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". The authors hypothesise that the loss of this gene may have been tolerated as felids became more carnivorous.

Genetic testing: Since all cats lack this gene, there is no need for any genetic testing

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
UGT1A6 UDP-glucuronosyltransferase 1A6 Felis catus C1 NC_018730.3 (216291583..216295369) UGT1A6 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Deficient acetaminophen glucuronidation UGT1A6 complex rearrangement "UGT1A6 is a pseudogene" 2000 10862526

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2011 Shrestha, B., Reed, JM., Starks, PT., Kaufman, GE., Goldstone, JV., Roelke, ME., O'Brien, SJ., Koepfli, KP., Frank, LG., Court, MH. :
Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory. PLoS One 6:e18046, 2011. Pubmed reference: 21464924. DOI: 10.1371/journal.pone.0018046.
2000 Court, MH., Greenblatt, DJ. :
Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms. Pharmacogenetics 10:355-69, 2000. Pubmed reference: 10862526.
1997 Court, MH., Greenblatt, DJ. :
Biochemical basis for deficient paracetamol glucuronidation in cats: an interspecies comparison of enzyme constraint in liver microsomes. J Pharm Pharmacol 49:446-9, 1997. Pubmed reference: 9232546.
Court, MH., Greenblatt, DJ. :
Molecular basis for deficient acetaminophen glucuronidation in cats. An interspecies comparison of enzyme kinetics in liver microsomes. Biochem Pharmacol 53:1041-7, 1997. Pubmed reference: 9174118.
1984 Savides, MC., Oehme, FW., Nash, SL., Leipold, HW. :
The toxicity and biotransformation of single doses of acetaminophen in dogs and cats. Toxicol Appl Pharmacol 74:26-34, 1984. Pubmed reference: 6729821.
1972 Capel, ID., French, MR., Millburn, P., Smith, RL., Williams, RT. :
The fate of (14C)phenol in various species. Xenobiotica 2:25-34, 1972. Pubmed reference: 4211177.
Davis, LE., Westfall, BA. :
Species differences in biotransformation and excretion of salicylate. Am J Vet Res 33:1253-62, 1972. Pubmed reference: 5022404.
1958 Robinson, D., Williams, R.T. :
Do cats form glucuronides? Biochemical journal 68:23–24, 1958.

Edit History


  • Created by Frank Nicholas on 21 Jul 2011
  • Changed by Frank Nicholas on 17 Nov 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 17 Sep 2012