Inhibition of the human platelet cyclooxygenase response by the naturally occurring phenazine derivative, 1-hydroxyphenazine

Abstract

The phenazine derivative, 1-hydroxyphenazine (OHP), is produced in vivo by Pseudomonas aeruginosa, an organism that colonises the airways of patients with cystic fibrosis. While known to inhibit leukotriene production by human neutrophils, the effects of OHP on cyclooxygenase pathways have not previously been reported. We used [3H] arachidonic acid (AA) under conditions of concurrent labelling-stimulation or pre-labelling for one hour followed by stimulation to determine the effects of OHP on the production of cyclooxygenase metabolites by human platelets stimulated with the calcium ionophore, A23187. Thromboxane B2 (TxB2) and 12-hydroxyheptadecatrienoic acid (HHT) production was inhibited in a dose-dependent manner by OHP using either pre-labelled or concurrently labelled platelets. However, production of 12-hydroxyeicosatetraenoic acid (12-HETE) was not diminished. Determination of the amount of total free label (AA+non-esterified AA metabolites) after stimulation of pre-labelled platelets indicated a dose-dependent inhibition of the release of AA from phospholipid by OHP. This was reflected in a corresponding increase in phospholipid AA content. These data indicate that phenazine derivatives of bacterial origin exhibit complex interactions with pathways of arachidonic acid metabolism in host cells. These effects may prove to be of pharmacological importance.