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Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors.
MedLine Citation:
PMID:  20548327     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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 n-3 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 n-3 fatty acids.
Authors:
W Liu; E M Poole; C M Ulrich; R J Kulmacz
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Publication Detail:
Type:  Journal Article     Date:  2010-06-15
Journal Detail:
Title:  The pharmacogenomics journal     Volume:  11     ISSN:  1473-1150     ISO Abbreviation:  Pharmacogenomics J.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101083949     Medline TA:  Pharmacogenomics J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  337-47     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
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