Transport and Elimination of Cysteinyl Leukotrienes

Universitat, D-8000Munchen70,WestGermany 1 Leukotriene elimination viabile andurine isan important mechanism ofinactivation forthese potent lipid mediators. We investigated whether theelimination ofcysteinyl leukotrienes isa targetfortheaction ofleukotriene receptor antagonists. 2 Experiments were performed inmaleratsunderdeepthiopentone anaesthesia. Thebile ductandthe urinary bladder werecannulated. Tritium labelled leukotrienes andleukotriene receptor antagonists were given viacentral venous catheters. Elimination ofleukotrienes produced invivowas studied following stimulation ofendogenous leukotriene biosynthesis byoperative trauma.3H-leukotriene metabolites were identified byh.p.l.c. analysis. Leukotrienes produced invivo weremeasured bycombined useofh.p.l.c. and RIA. 3 Undercontrol conditions, 49+ 12%oftheinjected 3H-leukotriene radioactivity was recovered inbile and1 + 0.8%inurine within 90min.Operative traumaresulted ininitial hepatobiliary secretion of 887+ 206pmolkg- h- oftheendogenous leukotriene metabolite N-acetyl leukotriene E4(LTE4NAc). 4 FPL 55712strongly inhibited hepatobiliary elimination of3H-leukotriene radioactivity ina dosedependent manner after i.v. injection of[3H]-LTC4, [3H]-LTD4 or [3H]-LTE4, respectively. Biliary [3H]-LTD4 was reduced mosteffectively. Theleukotriene antagonist potently prevented biliary elimination ofLTE4NAcproduced invivo. Bileflowandelimination frombloodintobile of[3H]-ouabain werealso impaired byFPL55712, buttoalesser extent. 5 LY 163443reduced biliary [3H]-LTD4 after i.v. administration of[3H]-LTD4. However, thetotal elimination of3H-leukotriene metabolites intobile was notsignificantly inhibited bythedrug. 6 MK-571reduced thebiliary concentration oftracerafter administration of3H-leukotrienes most potently withrespect to[3H]-LTD4. Incontrast, thetotal recoveryof3H-leukotrienes inbile tended to increase. Thisisexplained byadrug-induced increase inbile flow. 7 Urinary elimination of3H-leukotrienes, quantitatively less important intherat, was notsignificantly influenced bytheleukotriene receptor antagonists. Recovery of3H-leukotriene radioactivity inliver and kidneys was quantitatively insignificant. 8 Fromour data, we conclude thatleukotriene receptor antagonists havethepotential toaffect leukotriene elimination bya mechanism notnecessarily related toreceptor blockade. Inhibition ofelimination bythereceptor antagonists may prolong thebiological half life ofleukotrienes. Thiseffect may counteract theantagonistic properties ofthese drugs.

Leukotriene D4

Leukotriene C4

Leukotriene E4

Leukotriene receptor

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Leukotriene D4-metabolizing activity of human neutrophils.

Ensho (1987)

Isao Nagaoka Tatsuhisa Yamashita

Leukotriene D4-metabolizing activity was studied using human neutrophils. Leukotriene D4 was rapidly converted to leukotriene E4 during incubation with intact neutrophils. The subcellular localization of leukotriene D4-metabolizing enzyme was examined, and leukotriene D4-metabolizing activity was found to be present in the particulate fraction which consists of cell surface membrane and granules, but not in the nuclear and cytosol fractions. When neutrophils were modified chemically with diazotized sulfanilic acid, a poorly permeant reagent which inactivates cell surface enzymes selectively, the leukotriene D4-metabolizing activity of intact neutrophils was significantly inhibited. When neutrophils were stimulated with phorbol myristate acetate, a secretagogue, leukotriene D4-metabolizing activity was found to be released extracellularly. Among enzyme inhibitors examined, o-phenanthroline, a metal chelator strongly inhibited both the leuko-triene D4-metabolizing activities of intact neutrophils and extracellularly released enzyme. These results would suggest that leukotriene D4-metabolizing metalloenzymes which convert leukotriene D4 to leukotriene E4, are located on the cell surface membrane and in the granules of human neutrophils.

Leukotriene D4

Leukotriene E4

Leukotriene C4

Leukotriene B4

10.2492/jsir1981.7.339

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Studies on the leukotriene D4-metabolizing enzyme of rat leukocytes, which catalyzes the conversion of leukotriene D4 to leukotriene E4

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism (1987)

Isao Nagaoka Tatsuhisa Yamashita

Leukotriene C4

Leukotriene D4