Glucuronidation

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Cats have a uniquely carnivorous diet and, as a result of lack of exposure to plant-based toxins (phytoalexins), have presumably lost the need to metabolise these toxins via a process known as glucuronidation, which is common in most herbivores and omnivores[1]. This idiosyncrasy of feline hepatic physiology is presumed to be the result of pseudogenization of the gene encoding UDP-glucuronosyltransferase (UGT), a major phenol detoxification enzyme[2].

There are usually two methods of detoxifying endogenously-produced and exogenous drugs and chemicals. The first common methods of excreting toxic compounds in the cat involve circulatory process within the bloodstream which utilises Phase I processes involving Cytochrome-P450. This process converts most water-soluble drugs and endogenous toxins to metabolites that are usually excreted via the feline kidney. Lipid-soluble drugs often require metabolism by glucuronidation, a process first involving involving oxidation, reduction or hydrolysis[3].

Phase II process of drug and toxin metabolism involves conjugation of lipid-soluble toxins and drugs with natural substrates such as glutathione or glucuronic acid (hence the term glucuronidation)[4]. Cats have a deficiency certain enzymes, glucuronyl transferases, which are responsible for glucuronidation, and hence their reduced ability to metabolise certain phenolic drugs such as aspirin, benzoic acid, serotonin[5], acetaminophen (paracetamol)[6] and meloxicam[7].

This makes the cat uniquely sensitive to certain medications, which at doses given at an equivalent dose to dogs is often fatal due to the slow metabolic clearance of these drugs and increased levels during excretion.

Compensatory metabolism is seen in cats. For example, sulphation and acetylation of drugs is well developed in cats.

References

  1. Court MH & Greenblatt DJ (2000) 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(4):355-369
  2. Shrestha B et al (2011) 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(3):e18046
  3. Chandler, EA et al (2008) Feline Medicine and Therapeutics. J Wiley & Sons. pp: 3-4
  4. Court MH & Greenblatt DJ (1997) Molecular basis for deficient acetaminophen glucuronidation in cats. An interspecies comparison of enzyme kinetics in liver microsomes. Biochem Pharmacol 53(7):1041-1047
  5. Krishnaswamy S et al (2004) Evaluation of 5-hydroxytryptophol and other endogenous serotonin (5-hydroxytryptamine) analogs as substrates for UDP-glucuronosyltransferase 1A6. Drug Metab Dispos 32(8):862-869
  6. Tanaka N et al (2006) cDNA cloning and characterization of feline CYP1A1 and CYP1A2. Life Sci 79(26):2463-2473
  7. Lascelles BD et al (2007) Nonsteroidal anti-inflammatory drugs in cats: a review. Vet Anaesth Analg 34(4):228-250