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Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro.
J Pharmacol Exp Ther. 1984 Nov; 231(2):224-9.JP

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 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.

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Publisher Full Text

Authors

Snyder DW
No affiliation info available
Aharony D
No affiliation info available
Dobson P
No affiliation info available
Tsai BS
No affiliation info available
Krell RD
No affiliation info available

MeSH

AminopeptidasesAnimalsCarbacholCysteineDose-Response Relationship, DrugGuinea PigsHistamineIn Vitro TechniquesLeukotriene E4MaleMuscle ContractionSRS-ASerineTracheagamma-Glutamyltransferase

Pub Type(s)

Journal Article

Language

eng

PubMed ID

6149304

Citation

Snyder, D W., et al. "Pharmacological and Biochemical Evidence for Metabolism of Peptide Leukotrienes By Guinea-pig Airway Smooth Muscle in Vitro." The Journal of Pharmacology and Experimental Therapeutics, vol. 231, no. 2, 1984, pp. 224-9.
Snyder DW, Aharony D, Dobson P, et al. Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro. J Pharmacol Exp Ther. 1984;231(2):224-9.
Snyder, D. W., Aharony, D., Dobson, P., Tsai, B. S., & Krell, R. D. (1984). Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro. The Journal of Pharmacology and Experimental Therapeutics, 231(2), 224-9.
Snyder DW, et al. Pharmacological and Biochemical Evidence for Metabolism of Peptide Leukotrienes By Guinea-pig Airway Smooth Muscle in Vitro. J Pharmacol Exp Ther. 1984;231(2):224-9. PubMed PMID: 6149304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro. AU - Snyder,D W, AU - Aharony,D, AU - Dobson,P, AU - Tsai,B S, AU - Krell,R D, PY - 1984/11/1/pubmed PY - 1984/11/1/medline PY - 1984/11/1/entrez SP - 224 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 231 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/6149304/Pharmacological_and_biochemical_evidence_for_metabolism_of_peptide_leukotrienes_by_guinea_pig_airway_smooth_muscle_in_vitro_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6149304 DB - PRIME DP - Unbound Medicine ER -