Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs

Joel E. Wilson, Naduviladath V. Chandrasekharan, Kenneth D. Westover, Kendra B. Eager, Daniel L. Simmons

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Objective - To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). Sample Population - Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. Procedure - 11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50% of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. Results - Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. Conclusions and Clinical Relevance - Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.

Original languageEnglish (US)
Pages (from-to)810-818
Number of pages9
JournalAmerican Journal of Veterinary Research
Volume65
Issue number6
DOIs
StatePublished - Jun 2004

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Cyclooxygenase 1
nonsteroidal anti-inflammatory agents
prostaglandin synthase
Cyclooxygenase 2
Isoenzymes
Canidae
isozymes
Anti-Inflammatory Agents
Prostaglandin-Endoperoxide Synthases
nimesulide
Dogs
dogs
Etodolac
Pharmaceutical Preparations
Cyclooxygenase 2 Inhibitors
Tissue Distribution
Northern Blotting
Enzymes
Western Blotting
Meclofenamic Acid

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs. / Wilson, Joel E.; Chandrasekharan, Naduviladath V.; Westover, Kenneth D.; Eager, Kendra B.; Simmons, Daniel L.

In: American Journal of Veterinary Research, Vol. 65, No. 6, 06.2004, p. 810-818.

Research output: Contribution to journalArticle

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title = "Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs",
abstract = "Objective - To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). Sample Population - Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. Procedure - 11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50{\%} of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. Results - Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. Conclusions and Clinical Relevance - Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.",
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AB - Objective - To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). Sample Population - Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. Procedure - 11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50% of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. Results - Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. Conclusions and Clinical Relevance - Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.

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