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

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

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.

0952-0600
111-119
Sampson, A. P.
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
Evans, J. M.
2a88ab49-5f69-44d9-b287-c24bbcc74af9
Garland, L. G.
5f37b588-8941-436e-80d0-8686e85b8b5f
Piper, P. J.
7d88e87e-c5a4-4dcb-b561-89340bd49778
Costello, J. F.
53748fbc-3a08-4ebb-b5db-278bac65c9b1
Sampson, A. P.
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
Evans, J. M.
2a88ab49-5f69-44d9-b287-c24bbcc74af9
Garland, L. G.
5f37b588-8941-436e-80d0-8686e85b8b5f
Piper, P. J.
7d88e87e-c5a4-4dcb-b561-89340bd49778
Costello, J. F.
53748fbc-3a08-4ebb-b5db-278bac65c9b1

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).

Record type: Article

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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Published date: 1990
Additional Information: Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

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Local EPrints ID: 455265
URI: http://eprints.soton.ac.uk/id/eprint/455265
ISSN: 0952-0600
PURE UUID: 0a4607fb-26b2-4ce2-883b-a20011245cdd

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Date deposited: 15 Mar 2022 18:09
Last modified: 27 Jul 2022 16:36

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Contributors

Author: A. P. Sampson
Author: J. M. Evans
Author: L. G. Garland
Author: P. J. Piper
Author: J. F. Costello

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