Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors

W. Liu, E. M. Poole, C. M. Ulrich, R. J. Kulmacz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was 20% lower in 488G and 20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed 20% less and 511A showed 20% more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n3 fatty acids.

Original languageEnglish (US)
Pages (from-to)337-347
Number of pages11
JournalPharmacogenomics Journal
Volume11
Issue number5
DOIs
StatePublished - Oct 1 2011

Fingerprint

Cyclooxygenase Inhibitors
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Anti-Inflammatory Agents
Omega-3 Fatty Acids
nimesulide
Proteins
Fatty Acids
Pharmaceutical Preparations
Eicosapentaenoic Acid
Cyclooxygenase 2 Inhibitors
Recombinant Proteins
Colorectal Neoplasms

Keywords

  • arachidonic acid
  • cyclooxygenase
  • eicosapentaenoic acid
  • nonsteroidal antiinflammatory drugs
  • prostaglandin H synthase-2 polymorphisms

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors. / Liu, W.; Poole, E. M.; Ulrich, C. M.; Kulmacz, R. J.

In: Pharmacogenomics Journal, Vol. 11, No. 5, 01.10.2011, p. 337-347.

Research output: Contribution to journalArticle

@article{71e021b2bce4441f8665a3e6fc97d427,
title = "Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors",
abstract = "The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was 20{\%} lower in 488G and 20{\%} higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60{\%} higher residual COX activity; 511A also showed up to 70{\%} higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed 20{\%} less and 511A showed 20{\%} more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n3 fatty acids.",
keywords = "arachidonic acid, cyclooxygenase, eicosapentaenoic acid, nonsteroidal antiinflammatory drugs, prostaglandin H synthase-2 polymorphisms",
author = "W. Liu and Poole, {E. M.} and Ulrich, {C. M.} and Kulmacz, {R. J.}",
year = "2011",
month = "10",
day = "1",
doi = "10.1038/tpj.2010.49",
language = "English (US)",
volume = "11",
pages = "337--347",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors

AU - Liu, W.

AU - Poole, E. M.

AU - Ulrich, C. M.

AU - Kulmacz, R. J.

PY - 2011/10/1

Y1 - 2011/10/1

N2 - The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was 20% lower in 488G and 20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed 20% less and 511A showed 20% more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n3 fatty acids.

AB - The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was 20% lower in 488G and 20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed 20% less and 511A showed 20% more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n3 fatty acids.

KW - arachidonic acid

KW - cyclooxygenase

KW - eicosapentaenoic acid

KW - nonsteroidal antiinflammatory drugs

KW - prostaglandin H synthase-2 polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=80053573006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053573006&partnerID=8YFLogxK

U2 - 10.1038/tpj.2010.49

DO - 10.1038/tpj.2010.49

M3 - Article

C2 - 20548327

AN - SCOPUS:80053573006

VL - 11

SP - 337

EP - 347

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 5

ER -