Biochemical basis for deficient paracetamol glucuronidation in cats: an interspecies comparison of enzyme constraint in liver microsomes.
Unlike most other mammalian species, domestic cats glucuronidate phenolic compounds poorly and are therefore highly susceptible to the toxic side effects of many drugs, including paracetamol. In this study, we evaluated the role of enzyme constraint, a characteristic that limits the activity of all uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, in the aetiology of this species-dependent defect of drug metabolism. Detergent activation experiments were performed using hepatic microsomes from cats (4), dogs (4), man (4), and 6 other mammalian species (1 liver each). In addition, we used microsomes from Gunn rats which are sensitive to paracetamol toxicity because of a genetic defect affecting all family 1 UGTs. Increase in paracetamol-UGT activity at optimum concentrations of detergent was used as an index of enzyme constraint. Native activity (measured in the absence of detergent) was less than one-sixth in cats compared with other species. Optimum detergent treatment tended to enhance rather than abolish this difference, however, indicating relatively lower levels of constraint of paracetamol-UGT in cats compared with other species. Similarly, detergent treatment failed to reduce the native activity difference between homozygous mutant and normal Gunn rats. Initially CHAPS (3-(3-cholamidopropyl)-dimethylammonio-1-propanesulphonic acid) was used as the detergent activator; in 3 of 4 microsomal preparations from man, however, inhibition rather than activation was observed at all detergent concentrations used. Studies were repeated using the non-ionic detergent, Brij 58 (polyoxyethylene 20-cetyl ether), which resulted in similar although more profound activation and no inhibition. We conclude that deficient paracetamol glucuronidation in cats does not result from increased paracetamol-UGT constraint in this species compared with other mammalian species. Other causes, such as differences in enzyme protein concentration or substrate affinity might be responsible.
Court
M H
MH
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Greenblatt
D J
DJ
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D002415:Cats / Q000378:metabolism*; D002417:Cattle; D002592:Cetomacrogol / Q000494:pharmacology; D002793:Cholic Acids / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006736:Horses; D006801:Humans; D008251:Macaca; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D011817:Rabbits; D051381:Rats; D011911:Rats, Gunn; D013045:Species Specificity; D013501:Surface-Active Agents / Q000494:pharmacology; D013552:Swine
D018712:Analgesics, Non-Narcotic; D002793:Cholic Acids; D003902:Detergents; D013501:Surface-Active Agents; D000082:Acetaminophen; D002592:Cetomacrogol; D014453:Glucuronosyltransferase; C028213:3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate