PHARMACOLOGICAL AND BIOCHEMICAL-EVIDENCE FOR METABOLISM OF PEPTIDE LEUKOTRIENES BY GUINEA-PIG AIRWAY SMOOTH-MUSCLE INVITRO

  • 1 January 1984
    • journal article
    • research article
    • Vol. 231  (2) , 224-229
Abstract
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 animopeptidase inhibitor, L-cysteine and the .gamma.-glutamyl transpeptidase inhibitor, L-serine borate, on peptide LT concentration-responses 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 an nonspecific effect of these inhibitors on airway smooth muscle. In the absence of enzyme inhibitors the peptide LT were equipotent; whereas in their presence the relative order of potency was LTC4 = LTD4 > 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 [4H]LTC4 was blocked by L-serine borate in a concentration-related manner (IC50 = 3.4 .+-. 0.5 mM, mean .+-. S.E.M. [standard error of the mean], 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.