An alternative pathway for metabolism of leukotriene D-4: effects on contractions to cysteinyl-leukotrienes in the guinea-pig trachea

1 Contractions of guinea-pig tracheal preparations to cysteinyl-leukotriene s (LTC4, LTD4 and LTE4) were characterized in organ baths, and cysteinyl-le ukotriene metabolism was studied using radiolabelled agonists and RP-HPLC s eparation. 2 In the presence of S-hexyl GSH (100 muM) the metabolism of [H-3]-LTC4 int o [H-3]-LTD4 was inhibited and the LTC4-induced contractions were resistant to CysLT(1) receptor antagonism but inhibited by the dual CysLT(1)/CysLT(2 ) receptor antagonist BAY u9773 (0.3-3 muM) with a pA(2)-value of 6.8 +/- 0 .2. 3 In the presence of L-cysteine (5 mM), the metabolism of [H-3]-LTD4 in to [H-3]-LTE4 was inhibited and the LTD4-induced contractions were inhibite d by the CysLT1 receptor antagonist ICI 198,615 (1 - 10 nm) with a pA(2)-va lue of 9.3 +/- 0.2. However, at higher concentrations of ICI 198,615 (30-30 0 nm) a residual contraction to LTD4 was unmasked, and this response was in hibited by BAY u9773 (1 - 3 muM). 4 In the presence of the combination of S-hexyl GSH with L-cysteine, the LT D4-induced contractions displayed the characteristics of the LTC4 contracti le responses, i.e. resistant to CysLT(1) receptor antagonism, increased max imal contractions and slower thne-course. This qualitative change of the LT D4-induced contraction was also observed in the presence of S-decyl GSH (10 0 muM), GSH (10 mm) and GSSG (10 mM). 5 S-hexyl GSH, S-decyl GSH, GSH and GSSG all stimulated a formation or[H-3] -LTC4 from [H-3]-LTD4. 6 In conclusion, GSH and GSH-related compounds changed the pharmacology of the LTD4-induced contractions by stimulating the conversion of LTD4 into LT C4- Moreover, the results indicate that, in addition to the metabolism of L TC4 into LTD4 and LTE4, also the formation of LTC4 from LTD4 may regulate c ysteinyl-leukotriene function.