The generation and metabolism of leukotrienes in the ionophore-stimulated blood of normal and asthmatic subjects

Sampson, A. P., Evans, J. M., Garland, L. G., Piper, P. J. and Costello, J. F. (1990) The generation and metabolism of leukotrienes in the ionophore-stimulated blood of normal and asthmatic subjects. Pulmonary Pharmacology, 3 (3), 111-119. (doi:10.1016/0952-0600(90)90041-G).

Abstract

The generation and metabolism of leukotrienes (LTs) 1341 C₄, D4, and E₄ were studied in vitro in the A23187-stimulated whole blood of normal (N) and atopic asthmatic (AA) human subjects. Using a combination of reversed-phase high performance liquid chromatography and radioimmunoassay, we have demonstrated that the blood cells of atopic asthmatic patients have an enhanced ability to release LTB4 and LTC4 when compared to those of normal subjects. The release of LTB₄ and LTC₄ in response to ionophore is dose- and time-dependent. Half-maximal doses of ionophore caused the generation of high, sustained levels of LTB₄, which are significantly higher in the AA blood than in N blood. Incubations of ³H-LTB₄ in ionophore-stimulated N and AA blood revealed a slow metabolism to 20-OH-LTB₄ and 20-COON-LTB₄. LTC₄ is generated in smaller amounts than LTB4, with an early peak after 10 min which is significantly higher (p < 0.01) in the AA blood compared to the N blood. Subsequent metabolism of LTC₄ elicits significantly greater amounts of LTD₄, and consistently higher levels of LTE₄, in the AA blood. Parallel incubations of 3H-LTC₄ in ionophore-stimulated N and AA blood demonstrated rapid metabolism of LTC4 by the glutathione detoxification pathway. The elevated production of LTB₄ and LTC₄ in AA blood was not accounted for by differences in leukocyte sub-type counts in the two groups, nor by differences in their rates of catabolism. The novel, selective 5-lipoxygenase inhibitor BW A4C [N-(3-phenoxycinnamyl) acetohydroxamic acid] caused dose-dependent inhibition of LTB₄ and LTC₄ generation and was equipotent in N and AA blood.

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Contributors

Author: A. P. Sampson

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