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Vol. 299, Issue 2, 468-476, November 2001
Laboratory of Computational Biology and Risk Analysis (E.F.,
D.A.B.), Laboratory of Molecular Carcinogenesis (S.J.B., T.E.E.), and
Laboratory of Pulmonary Pathobiology (L.M.K., D.C.Z.), National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina
Cyclooxygenases (COX)-1 and -2 are the key enzymes in the conversion of
arachidonic acid to prostaglandins. COX-2 appears to play an emerging
role in inflammation and carcinogenesis. Nonsteroidal anti-inflammatory
drugs (NSAIDs) are used for the treatment of numerous diseases and
reduce the risk of developing colorectal cancer. Polymorphisms in the
COX-2 gene could alter enzyme expression, function, and/or the response
to NSAIDs. Therefore, they could modify individual risks for developing
cancer and other diseases or the occurrence of side effects or
sensitivity toward selective or nonselective COX inhibitors. We
sequenced the COX-2 gene of 72 individuals and identified rare
polymorphisms in the promoter and the coding region. A COX-2 molecular
model was used to locate the coding region polymorphisms relative to
functional sites in the protein, and the COX-2 V511A polymorphism was
very near to the active site. This variant protein was expressed, and
function was evaluated, but no difference was detected in metabolism of the COX-2 substrates, arachidonic acid, linoleic acid, and
2-arachidonyl glycerol, compared with the wild type. The
Km values for arachidonic acid showed no
differences between the COX-2 wild type and V511A mutant. Inhibition
with selective or nonselective COX inhibitors was essentially the same
for the two enzymes. The absence of functionally important
polymorphisms in the COX-2 gene may suggest that there has been
selective pressure against those single nucleotide polymorphisms because of the critical role of this enzyme in maintenance of homeostasis.
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