Biosynthesis of prostaglandins from 17(18)epoxy-eicosatetraenoic acid, a cytochrome P-450 metabolite of eicosapentaenoic acid.
Eicosapentaenoic acid (20:5(n - 3)) is oxygenated to 17S(18R)epoxyeicosatetraenoic acid (EpETE) by microsomes of monkey seminal vesicles, which also are rich in prostaglandin (PG) H synthase. The metabolism of racemic [14C]17(18)EpETE by PGH synthase of sheep vesicular glands was investigated in the present report. The two main metabolites were identified by GC-MS as 17(18)epoxyprostagland E2 (17(18)EpPGE2) and 17(18)EpPGF2 alpha. The structures were confirmed by chemical synthesis of these prostaglandins from PGE3. 17(18)EpPGE1 was synthesized from 17,18-dehydro-PGE1 by the same method. Alkali treatment of 17(18)EpPGE2 yielded 17(18)EpPGB2, which could be resolved by RP-HPLC into the 17R(18S) and 17S(18R) stereoisomers. The 17S(18R) stereoisomer was identified by co-chromatography with [14C]17S(18R)EpPGB2, which was formed by PGH synthase from biosynthetic [14C]17S(18R)EpETE. The 17(18)epoxyprostaglandins were found to be relatively unstable during acidic extractive isolation. 17(18)EpPGE1 and 17(18)EpPGE2 could not be detected in seminal vesicles of the cynomolgus monkey in significant amounts relative to 19-hydroxy-PGE1. Nevertheless, biosynthesis of 17(18)epoxyprostaglandins should be considered when the biological effects of 17S(18R)EpETE are investigated.
Oliw
E H
EH
Department of Pharmaceutical Pharmacology, Uppsala University Biomedical Centre, Sweden.
Okamoto
S
S
Hörnsten
L
L
Sato
F
F
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D011453:Prostaglandins / Q000096:biosynthesis*; D011456:Prostaglandins B / Q000096:biosynthesis; D011458:Prostaglandins E / Q000032:analysis / Q000096:biosynthesis / Q000138:chemical synthesis; D011460:Prostaglandins F / Q000096:biosynthesis; D012669:Seminal Vesicles / Q000737:chemistry
D001095:Arachidonic Acids; D011453:Prostaglandins; D011456:Prostaglandins B; D011458:Prostaglandins E; D011460:Prostaglandins F; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System