title: Lipoxygenase inhibitory activity of U-66,858 and its deacetylated metabolite U-68,244 in human whole blood.
abstract: The inhibitory effects of the semi-quinone U-66,858 and its metabolite U-68,244 on the ionophore-induced formation of leukotriene B4 (LTB4) were examined in human whole blood (WB). Preincubation of U-66,858 and U-68,244 for 1 min prior to challenge of blood with calcium ionophore A23187 resulted in IC50 values of 1080 +/- 644 and 820 +/- 442 nmol/L, respectively (NS). After 60 min preincubation, values were 250 +/- 85 and 270 +/- 79 nmol/L (NS). The activity of the lipoxygenase inhibitor AA-861 in this system was similar to that of U-66,858, while vitamin K and the sulphate conjugate of U-66,858 showed significant inhibition of LTB4 release only at micromolar concentrations. U-66,858 exhibited significant inhibition of thromboxane A2 release (p < 0.02) in a comparative study with the known cyclooxygenase (CO) inhibitor flurbiprofen. The metabolism of U-66,858 in contact with WB at 37 degrees C was monitored for 70 min using [14C]-labelled drug and reverse-phase HPLC, the majority of recovered radioactivity no longer in the form of U-66,858 being accounted for by U-68,244 and polar conjugates of U-66,858. Thus, U-66,858 is a potent inhibitor of LTB4 production in human whole blood and undergoes deacetylation to an initial metabolite with similar pharmacological potency. However, other metabolites of U-66,858 such as the sulphate conjugate, are relatively weak inhibitors of 5-lipoxygenase (5-LO) under similar conditions.
authors.affiliation: Immunopharmacology Group, Southampton General Hospital, Hampshire, U.K.
authors.forename: J A
authors.initials: JA
authors.lastname: Summers
authors.forename: A
authors.initials: A
authors.lastname: Bye
authors.forename: C
authors.initials: C
authors.lastname: Robinson
mesh_terms: D000328:Adult; D016227:Benzoquinones / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009284:Naphthols / Q000378:metabolism / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors
chemical_list: D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2; D013928:Thromboxane A2; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C057769:bunaprolast; C089204:U 68244