Pharmacogenomics of cyclooxygenases

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From: Pharmacogenomics(Vol. 16, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 13,956 words
Lexile Measure: 1950L

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Author(s): José AG Agúndez [*] aff1 aff2 , Miguel Blanca aff2 aff3 , José A Cornejo-García aff2 aff3 , Elena García-Martín aff2 aff4

Keywords:

COX-1; COX-2; cyclooxygenases; gene variants; pharmacogenomics; PTGS1; PTGS2; SNPs

A substantial part of the clinical relevance of cyclooxygenases 1 and 2 (prostaglandin-endoperoxide synthases [EC 1.14.99.1]), designated as COX-1 and COX-2, is related to the clinical use of pharmacological inhibition of these enzymes. The therapeutic benefits of COX inhibition by widely used drugs such as NSAIDs include the treatment of pain, fever and the symptoms of inflammation. In addition, COX enzymes are involved in prostanoid formation and are involved in several physiological and pathological situations [ 1-6 ]. COX-1 is considered as a constitutively expressed enzyme in most tissues, particularly in endothelium, platelets and monocytes. COX-2, however, is a proinflammatory enzyme; it has been shown that mediators of inflammation regulate the COX-2 enzyme both on transcriptional and post-transcriptional levels [7,8 ], and that overexpression of COX-2 is related to cancer risk [4,5 ].

The development of drugs which are specific COX-2 inhibitors was based on the assumption that most of the beneficial pharmacological effects of COX inhibition are related to the inhibition of COX-2, whereas most of the adverse reactions observed with COX inhibitors, and in particular gastrointestinal effects, are due to COX-1 inhibition [9 ]. However, the risks of pharmacological COX-2 inhibition are not yet fully understood, and growing evidence indicates that COX-2 inhibitors are not as safe as initially expected [10,11 ]. Similarly to pharmacological COX inhibition, factors that might influence COX activities or expression levels in vivo may modify the risks inherent to pharmacological treatments involving COX inhibition, and may also modify the clinical association of COX activity with human diseases.

Factors capable of modifying COX activity include gene variations which may modify basal expression, inducibility, structure and/or function of COX enzymes. COX-1 and COX-2 enzymes are encoded by the PTGS1 and PTGS2 genes, respectively. PTGS1 is located in chromosome 9, within the positions 9:125132824-125157982 and has five transcripts which encode five proteins containing between 156 and 599 amino acids [12 ]. PTGS2 is located in chromosome 1, within the positions 1:186640923-186649559 (reverse strand) and it has five transcripts. Only one out of these five PTGS2 transcripts encodes a functional protein of 604 amino acids, another transcript encodes an incomplete protein containing 161 amino acids, and the three remaining transcripts do not lead to any protein product [13 ]. The functional COX-1 and COX-2 enzymes are structurally similar, sharing about 63% of their amino acid sequences. Both have a molecular weight of about 71 kDa and share major functional regions [14 ]. A prominent structural difference is the presence of eight amino acids in the amino-terminus of COX-1, which are missing in the COX-2 enzyme. These eight amino acids seem to be determinant in the Vmax of the enzyme because when these are removed, the Vmax is reduced to one-third of that of the full COX-1 enzyme [15 ]. Gene variations affecting the PTGS1 and PTGS2 gene promoters and inducing...

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Gale Document Number: GALE|A411315281