Comparison of the effects of inhibitors of cytochrome P-450-mediated reations on human platelet aggregation and arachidonic acid metabolism |
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Authors: | Michael J Parnham Peter C Bragt Aalt Bast Frederick J Zijlstra |
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Institution: | 1. Department of Pharmacology, Medical Faculty, Erasmus University, Rotterdam, P.O. Box 1 738, 3 000 DR Rotterdam, The Netherlands;2. Department of Pharmacology, Faculty of Pharmacy, State University of Utrecht, Catharijnesingel 60, 3511 GH Utrecht The Netherlands |
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Abstract: | Metyrapone and SKF-525A, together with amphenone B, a structural analogue of metyrapone, which are all inhibitors of cytochrome P-450-mediated reactiors, were shown to inhibit the arachidonic acid-induced aggregation of human platelets. Amphenone B, like metyrapone, exhibited a type II (ligand) binding spectrum with rat liver microsomal cytochrome P-450, in contrast to SKF 525A which is a type I (substrate) binding agent. Independently of their type of binding spectra and of their maximum spectral change, however, the affinity of the three compounds for rat liver cytochrome P-450 showed a close proportional correlation with their platelet aggregation inhibitory potency. All three compounds inhibited the formation of 1?14C]thromboxane B2 from 1?14C]arachidonic acid by human platelets aggregated with collagen. The effect of metyrapone on the remaining labelled products suggested that it is a selective thromboxane synthesis inhibitor, while amphenone B exhibited activity reminiscent of cyclo-oxygenase inhibitors. SKF 525A produced complex effects possibly attributable to cyclo-oxygenase inhibition and enhanced lipid peroxidation, since it also enhanced platelet malonaldehyde formation, which the other two compounds inhibited. These data provide further support for a role of cytochrome P-450 in thromboxane synthesis and platelet aggregation. |
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Keywords: | Cytochrome P-450 Platelet aggregation Arachidonic acid metabolism Metyrapone Thromboxane synthesis |
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