Direct inhibition of cyclooxygenase pathway in platelets by tixocortol 21-pivalate: comparison with related structures, steroidal and non steroidal anti-inflammatory drugs.
Direct activity of the local anti-inflammatory steroid, tixocortol 21-pivalate (21 thioester derivative of cortisol) on metabolism of exogenous arachidonate by rabbit platelets was investigated in vitro. Tixocortol 21-pivalate inhibited generation of prostanoids from cyclooxygenase with an IC50 value of 19.6 microM without affecting the 12-lipoxygenase pathway. In this model, reference anti-inflammatory glucosteroids were ineffective, whereas indomethacin and aspirin inhibited the cyclooxygenase activity. Among tixocortol 21-pivalate related structures, tixocortol and its disulfide dimere or several other tixocortol esters exhibited a quite similar efficacy while S-methylation and subsequent S-oxydations of tixocortol abolished inhibitory activity. These results indicate that tixocortol 21-pivalate in contrast to other glucosteroids is able to act directly on cyclooxygenase pathway and that some specific chemical environment of the 21 thiol side chain are required for this inhibition.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D011817:Rabbits; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C019112:tixocortol pivalate; D006854:Hydrocortisone