Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 231; no. 2; pp. 224 - 229
• Main Authors: SNYDER, D. W, AHARONY, D, DOBSON, P, TSAI, B. S, KRELL, R. D
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.11.1984
• Subjects: Aminopeptidases - antagonists & inhibitors; Animals; Biological and medical sciences; Carbachol - pharmacology; Cysteine - pharmacology; Dose-Response Relationship, Drug; gamma-Glutamyltransferase - antagonists & inhibitors; Guinea Pigs; Histamine - pharmacology; In Vitro Techniques; Leukotriene E4; Male; Medical sciences; Muscle Contraction - drug effects; Pharmacology. Drug treatments; Respiratory system; Serine - pharmacology; SRS-A - analogs & derivatives; SRS-A - metabolism; SRS-A - pharmacology; Trachea - drug effects; Trachea - metabolism; Smooth muscle; Animal
• ISSN: 0022-3565; 1521-0103

It has been demonstrated that leukotriene (LT)C4 is metabolized to LTD4 via the action of the enzyme gamma-glutamyl transpeptidase. LTD4 is, in turn, converted by the enzyme aminopeptidase to LTE4. In the present study, the pharmacological effects of the aminopeptidase inhibitor, L-cysteine and the gamma-glutamyl transpeptidase inhibitor, L-serine borate, on peptide LT concentration-response curves were evaluated in isolated guinea-pig trachea. L-Cysteine (3 mM) enhanced the contractile activity of both LTC4 and LTD4. L-Serine borate (45 mM) enhanced the contractile activity of LTC4 without altering the response to LTD4. In contrast, neither L-cysteine nor L-serine borate consistently altered the concentration-response curves to LTE4, histamine or carbachol, which rules out a nonspecific effect of these inhibitors on airway smooth muscle. In the absence of enzyme inhibitors the peptide LTs were equipotent; whereas in their presence the relative order of potency was LTC4 = LTD4 greater than LTE4. Incubation of isolated guinea-pig trachea with [3H]LTC4 resulted in the formation of [3H]LTD4 and [3H]LTE4 with a proportional decrease in [3H]LTC4. The bioconversion of [3H]LTC4 was blocked by L-serine borate in a concentration-related manner (IC50 = 3.4 +/- 0.5 mM, mean +/- S.E.M., n = 3) and the formation of LTE4 was blocked by L-cysteine (10 mM). The results suggest that LTC4 is converted to LTD4 and subsequently to LTE4 by isolated guinea-pig trachea. The potency of LTC4 and LTD4 is increased when their transformation to LTE4 is prevented.