Effect of tert-butyl hydroperoxide on cyclooxygenase and lipoxygenase metabolism of arachidonic acid in rabbit platelets.
The effect of tert-butyl hydroperoxide (t-BOOH) on the formation of thromboxane (TX) B2, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) from exogenous arachidonic acid (AA) in washed rabbit platelets was examined. t-BOOH enhanced TXB2 and HHT formation at concentrations of 8 microM and below, and at 50 microM it inhibited the formation, suggesting that platelet cyclooxygenase activity can be enhanced or inhibited by t-BOOH depending on the concentration. t-BOOH inhibited 12-HETE production in a dose-dependent manner. When the platelets were incubated with 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) instead of AA, t-BOOH failed to inhibit the conversion of 12-HPETE to 12-HETE, indicating that the inhibition of 12-HETE formation by t-BOOH occurs at the lipoxygenase step. Studies utilizing indomethacin (a selective cyclooxygenase inhibitor) and desferrioxamine (an iron-chelating agent) revealed that the inhibitory effect of t-BOOH on the lipoxygenase is not mediated through the activation of the cyclooxygenase and that this effect of t-BOOH is due to the hydroperoxy moiety. These results suggest that hydroperoxides play an important role in the control of platelet cyclooxygenase and lipoxygenase activities.
Fujimoto
Y
Y
Department of Hygienic Chemistry, Osaka University of Pharmaceutical Sciences, Japan.
Takai
S
S
Matsuno
K
K
Sumiya
T
T
Nishida
H
H
Sakuma
S
S
Fujita
T
T
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D005296:Ferrous Compounds / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D008084:Lipoxygenase / Q000097:blood*; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D011794:Quercetin / Q000494:pharmacology; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis; D020122:tert-Butylhydroperoxide
D005231:Fatty Acids, Unsaturated; D005296:Ferrous Compounds; D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D016877:Oxidants; D010545:Peroxides; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D013929:Thromboxane B2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C021201:12-HPETE; D020122:tert-Butylhydroperoxide; D011794:Quercetin; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D003676:Deferoxamine; D007213:Indomethacin