Bioconversion of C-6 sulfidopeptide leukotrienes by the responding guinea pig ileum determines the time course of its contraction.

The naturally occurring sulfidopeptide leukotrienes, leukotriene (LT) C(4) (LTC(4)) [5(S)-hydroxy - 6(R) - S - glutathionyl - 7,9 - trans, 11,14 - cis - eicosatetraenoic acid] and its cysteinylglycine (LTD(4)) and cysteinyl (LTE(4)) analogs, which are derived by peptide cleavage, differ in the concentrations required to elicit comparable contractions of the guinea pig ileum, with respective potencies of 1.2:5:1. The effect of the ongoing bioconversion of LTC(4) and LTD(4) on the contractile response of the guinea pig ileum to each was determined by recording the pattern of the contraction and quantitating the initial agonist and its metabolic products. The contraction was elicited by radiolabeled agonist, and its conversion products were sampled at defined intervals and resolved by their retention times on reverse-phase high performance liquid chromatography. After a latent period of 60 s. LTC(4) initiated a linear response, followed by a slower, progressive response to a maximum level that was maintained without relaxation. The metabolic conversion of LTC(4) was <5% during the linear phase of contraction and complete inhibition of bioconversion of LTC(4) to LTD(4) by the presence of serine-borate complex did not alter the pattern of the spasmogenic response. As the maximum response in the presence of serine-borate complex was three-quarters of that obtained without the inhibitor of bioconversion, the predominant response was to LTC(4) itself. The spasmogenic response of the ileum to LTD(4) was immediate, linear to a maximum level, and immediately followed by a marked relaxation. That the failure of LTD(4) to sustain a contraction was due to its immediate, rapid, and quantitative conversion to the less potent LTE(4) was established by pharmacologically inhibiting and anatomically deleting the converting activity. In the presence of L-cysteine the conversion of LTD(4) to LTE(4) was largely inhibited and the maximum contractile response was well maintained. After anatomic removal of the mucosa that contained the LTD(4) dipeptidase activity, the longitudinal smooth muscle preparation gave a maximal response to LTD(4) that was fully maintained. Thus, bioconversion is not a prerequisite for the spasmogenic activity of LTC(4) and accounts for the transient response of the ileum to LTD(4).