Accelerative autoactivation of prostaglandin biosynthesis by PGG2.

Received October 24, 1978 Summary : Cyclooxygenase catalysis is stimulated by its product, PGG2, and by other lipid hydroperoxides. The endoperoxide, PGH , was not stimulatory. The results provide a direct demonstration of an essen & ial role for lipid hydroperoxides in prostaglandin biosynthesis, and show how the biosynthetic intermediate PGG2 has a positive accelerative effect. INTRODUCTION A bis-dioxygenation of unsaturated fatty acids by cyclooxygenase produces the endoperoxide which leads to the formation of all subsequent prostaglandins, thromboxanes and prostacyclin. Recent reviews have noted a variety of physiologic and pharmacologic mechanisms for the regulation of cyclooxygenase activity (l-3). For example, reductians in the available levels of the required heme cofactor and the substrates, oxygen and unesterified fatty acid, are known to reduce prostaqlandin formation in vitro. In addition, the extent of -~ product formation is limited by a self-inactivation of the cyclooxygenase (4,5) which perhaps protects aqainst overproduction of prostaglandins. Another important feature of the reaction mechanism is the requirement for a minimal level of peroxide to initiate and maintain cyclooxygenase catalysis. This peroxide requirement is not readily apparent in the routine cyclooxygenase assays and as a result, it can be easily overlooked. The requirement was clearly demonstrated when the removal of peroxide by additions of glutathione peroxidase (GSP) inhibited oxyqenation by crude (4,6) and purified (5) cyclooxygenase and interrupted prostaglandin biosynthesis already in Abbreviations: DDC, diethyldithiocarbamate; GSP, glutathione peroxidase; GSH, glutathione; HPET, hydroperoxyeicosatetraenoic acid; PGG2, prostaglandin Gp; PGH2, prostaglandin Hz.