Metabolism of Prostaglandin D₂ by 11-Ketoreductase in the Rabbit Liver

Abstract

In 1973, Nugteren and Hazelhof [1] described the formation of PGD₂ from endoperoxides (PGG₂ and PGH₂). Subsequently, PGD₂ has been found to be one of the major products of arachidonic acid cascade in many tissue and cell types [2]. Recently, several groups of investigators have demonstrated the transformation of PGH₂ to PGD₂ in brain homogenates [3, 4] and neuroblastoma cells [5]. The enzyme, PGD₂ synthetase, which catalyzed the conversion of PGH₂ to PGD₂, has been purified to homogeneity and clearly distinguished from that of glutathione-s-transferase [6]. It has been demonstrated that PGD₂ is released by platelets during aggregation [7]. PGD₂ has also been found to be a potent inhibitor of platelet aggregation, with a potency only less than that of prostacyclin (PGI₂) and its stable biologically active metabolite, 6-keto-PGE₁ [8, 9]. Although PGD₂ is not metabolized by the lung 15-hydroxyprostaglandin dehydrogenase in vitro [10, 11], Ellis and co-workers [12] have found that over two thirds of the PGD₂ metabolite of the monkey have the cyclo-pentane-1,3-diol structure of PGF_2α. They suggested that the infused PGD₂ may have been converted to PFG_2α by a possible enzymic route: 11-Ketoreductase, before it was further metabolized by 15-hydroxyprostaglandin dehydrogenase and β-oxidation. In addition, as early as 1974, Hensby [13] described the conversion of PGD₂ to PGF_2α in sheep blood in vitro.