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GP O'Neill, JA Mancini, S Kargman, J Yergey, MY Kwan, JP Falgueyret, M Abramovitz, BP Kennedy, M Ouellet and W Cromlish
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Human prostaglandin G/H synthase (hPGHS)-1 and hPGHS-2, key enzymes in the formation of prostanoids from arachidonic acid, were expressed at high levels in COS-7 cells using a T7 RNA polymerase/vaccinia virus expression system. The open reading frame of hPGHS-2 cloned into vaccinia virus without its natural 5' and 3' untranslated regions directed only low levels of hPGHS-2 enzyme activity in COS-7 cells. High-level hPGHS-2 expression was achieved by appending the 3' untranslated region of hPGHS-1 to the hPGHS-2 open reading frame, with subsequent expression of the hybrid mRNA using vaccinia virus. Enzymatically active recombinant hPGHS-1 and hPGHS-2 were present as glycosylated proteins in the microsomal fraction prepared from infected cells, whereas recombinant hPGHS-1 and hPGHS-2 prepared from the microsomal fraction of cells treated with tunicamycin, an inhibitor of N-linked glycosylation, were enzymatically inactive. The major prostanoid products formed by microsomes from COS-7 cells containing either recombinant hPGHS-1 or hPGHS-2 after incubation with arachidonic acid were prostaglandin D2 and E2, with lower levels of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha. A range of potencies were observed for various nonsteroidal anti-inflammatory drugs as inhibitors of prostaglandin E2 synthesis by hPGHS-1 and hPGHS-2. Recombinant hPGHS- 1 and hPGHS-2 both produced 15- and 11-hydroxyeicosatetraenoic acid (HETE) from arachidonic acid, with 15-HETE production by hPGHS-2 being stimulated 5-fold by preincubation with aspirin. Chiral phase high performance liquid chromatography analysis showed that aspirin-treated hPGHS-2 produced 15(R)-HETE, with no detectable 15(S)-HETE.
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