Effects of (1,6-di(O-carbamoyl)cyclohexanone oxime)hexane (RHC 80267) on prostaglandin biosynthesis and accumulation of diacylglycerol and arachidonic acid in rabbit iris.
The effects of RHC 80267, (1-6-di(O-carbamoyl)cyclohexanone oxime)hexane, a diacylglycerol (DG) lipase inhibitor, on the DG lipase pathway and on arachidonic acid (AA) metabolism were investigated in the iris muscle. Incubation of the iris for 30 min at 37 degrees resulted in a loss of AA from phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine of 40, 25, and 32% respectively. It was found that the drug inhibited the activity of DG lipase in the iris microsomal fraction and it increased the accumulation of DG, AA and other glycerolipids in iris muscle prelabeled with [14C]AA, presumably by inhibiting this enzyme. Under the same experimental conditions, the drug increased the accumulation of DG and AA in the tissue in a dose- and time-dependent manner, and it inhibited the synthesis of prostaglandin E2 (PGE2) and PGF2 alpha by iris and iris microsomes in a dose-dependent manner. The data presented indicate that RHC 80267 has nonspecific effects on glycerolipid and AA metabolism in this tissue. We conclude that, while the drug does inhibit DG lipase in the intact iris, the present findings that it increased the accumulation of glycerolipids and AA and that it inhibited the biosynthesis of PGs in this tissue throw some doubt on its use in studies on the mechanism of AA release from membrane phosphoinositides for PG synthesis.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002417:Cattle; D003510:Cyclohexanes / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism*; D015232:Dinoprostone; D005989:Glycerides / Q000378:metabolism*; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000096:biosynthesis; D011817:Rabbits
D001095:Arachidonic Acids; D003510:Cyclohexanes; D003512:Cyclohexanones; D004075:Diglycerides; D005989:Glycerides; D010743:Phospholipids; D011453:Prostaglandins; D011458:Prostaglandins E; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D008071:Lipoprotein Lipase; D015232:Dinoprostone