Abstract
Cell-free 100,000 g supernatants from liver, kidney, lung and caecum of rat, rabbit and guinea-pig were compared for their ability to transform prostaglandins F 2α, D 2, E 2 and 9α, 11β-prostaglandin F 2 (11epi-PGF 2α) to metabolic products. Experiments utilized multitritiated substrate PGs, with assessment of biotransformation by TLC, HPLC and GC/MS. PGF 2α was converted via the sulphasalazine analogue-inhibitable NAD +-dependent 15-hydroxy-prostaglandin dehydrogenase pathway (15-PGDH), with high activity (>5 pmol/min/mg protein) in all 12 systems except rat and rabbit liver (e.g. guinea-pig kidney and rat caecum both 64 pmol/min/mg; rat liver 0.3 pmol/min/mg), forming 15-keto and 13,14-dihydro-15-keto metabolites as determined by TLC, HPLC and GC/MS. Prostaglandin D 2 was not transformed in similar fashion in NAD +- or NADP +-supplemented incubations in any of the 12 cytosolic systems. However, PGD 2 was converted to a single product identified by TLC, HPLC and GC/MS as 9α, 11β-PGF 2 in certain of the systems when supplemented with an NADPH regenerating system, with high activity in guinea-pig kidney (55.0 pmol/min/mg), guinea-pig liver (27.5 pmol/min/mg) and rabbit liver (13.7 pmol/min/mg) and less than 5 pmol/min/mg in 8 of the remaining 9 systems. This stereospeciflc 11-ketoreductase of rabbit and guinea-pig liver was stable to 10 min heating at 50°, dialysis, storage at −20° and repeated freeze/thawing but was not inhibited by sulphasalazine analogues. The 11-ketoreductase had a markedly different tissue profile from PGE 2 9-ketoreductase, which was shown to convert PGE 2 stereospecifically to 9α, 11α-prostaglandin F 2 (PGF 2α) and was present at highest activity in rabbit liver and kidney. Evidence was obtained that 9α, 11β-PGF 2 was actively transformed by the sulphasalazine-inhibitable 15-PGDH pathway at approximately one third of the rate of PGF 2α with high activity in several cytosolic systems (e.g. rat caecum, guinea-pig liver and kidney), suggesting that further transformation in vivo of this biologically active product of PGD 2 metabolism could be initiated by this route.
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