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CELLULAR AND MOLECULAR

Cloning, Expression, and Functional Characterization of Human Cyclooxygenase-1 Splicing Variants: Evidence for Intron 1 Retention

Analgesics (N.Q., S.-P.Z., T.L.R., C.M.F.) and Oncology (J.M.M.) Research Teams, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development LLC, Spring House, Pennsylvania

Recently, a splicing variant of cyclooxygenase (COX)-1, arising via the retention of its intron 1, was identified in canine. It was called COX-3 and was reported to be differentially sensitive to inhibition by various nonsteroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen (Chandrasekharan et al., 2002). However, the existence of an orthologous splicing variant in human tissues has been questioned due to a reading frame shift and premature termination. In this study, we first confirmed the existence of intron 1-retained COX-1 in certain human tissues at both the mRNA and protein levels. Molecular biology studies revealed that three distinct COX-1 splicing variants exist in human tissues. The most prevalent of these variants, called COX-1b₁, arises via retention of the entire 94 base pair (bp) of intron 1, leading to a shift in the reading frame and termination at bp 249. However, the other two variant types, called COX-1b₂ and COX-1b₃, retain entire intron 1, but they are missing a nucleotide in one of two different positions, thereby encoding predicted full-length and likely COX-active proteins. Functional studies revealed that the COX-1b₂ is able to catalyze the synthesis of prostaglandin F₂ from arachidonic acid with K_m and V_max values of 0.54 µM and 3.07 pmol/mg/min, respectively. However, no significant differential selectivity for inhibition by selected NSAIDs was observed. Accordingly, we conclude that intron 1-retained human COX-1 is not likely to be the therapeutic target of acetaminophen or a candidate of COX-3.

Address correspondence to: Dr. Ning Qin, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, P.O. Box 776, Welsh and McKean Roads, Spring House, PA 19477-0776. E-mail: nqin{at}prdus.jnj.com

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