BIOCONVERSION OF C-6 SULFIDOPEPTIDE LEUKOTRIENES BY THE RESPONDING GUINEA-PIG ILEUM DETERMINES THE TIME COURSE OF ITS CONTRACTION
BIOCONVERSION OF C-6 SULFIDOPEPTIDE LEUKOTRIENES BY THE RESPONDING GUINEA-PIG ILEUM DETERMINES THE TIME COURSE OF ITS CONTRACTION
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DOI：
10.1172/jci110845
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发表时间：
1983-01-01
影响因子：
15.9
通讯作者：
AUSTEN, KF
中科院分区：
文献类型：
--
作者：
KRILIS, S;LEWIS, RA;AUSTEN, KF
天然存在的硫多肽白三烯，白三烯（LT） C4 (LTC4) [5(S)-羟基-6(R)-S-谷胱甘肽-7,9-反式，11,14-顺式-二十碳四烯酸]及其半胱氨酸甘氨酸（LTD4）和半胱氨酸（LTE4）类似物，通过肽裂解得到，在引起豚鼠回肠类似收缩所需的浓度不同，各自的效力为1.2:5:1。通过记录收缩模式和定量测定初始激动剂及其代谢产物，确定LTC4和LTD4持续生物转化对豚鼠回肠对各自收缩反应的影响。收缩是由放射性标记的激动剂引起的，其转化产物在规定的时间间隔取样，并在反相高效液相色谱上通过其保留时间进行分离。经过60 s的潜伏期后，LTC4开始了线性反应，随后是一个较慢的渐进式反应，达到最大水平，没有松弛。在收缩的线性阶段，LTC4的代谢转化< 5%，丝氨酸-硼酸盐复合物的存在完全抑制LTC4到LTD4的生物转化并没有改变痉挛反应的模式。由于丝氨酸-硼酸盐复合物存在时的最大反应是没有生物转化抑制剂时的3/4，因此主要的反应是对LTC4本身的反应。回肠对LTD4的痉挛性反应是立即的，线性到最大水平，随后立即出现明显的松弛。LTD4维持收缩的失败是由于其立即、快速和定量地转化为效力较低的LTE4，这是通过药理学抑制和解剖上删除转化活性来建立的。在l -半胱氨酸存在的情况下，LTD4向LTE4的转化被很大程度地抑制，最大收缩反应得以很好地维持。解剖去除含有LTD4二肽酶活性的粘膜后，纵向平滑肌制备对LTD4的反应最大，并得到充分维持。生物转化并不是LTC4致痉挛活性的先决条件，也解释了回肠对LTD4的短暂反应。
The naturally occurring sulfidopeptide leukotrienes, leukotriene (LT) C4 (LTC4) [5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans,11,14-cis-eicosatetraenoic acid] and its cysteinylglycine (LTD4) and cysteinyl (LTE4) 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 LTC4 and LTD4 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, LTC4 initiated a linear response, followed by a slower, progressive response to a maximum level that was maintained without relaxation. The metabolic conversion of LTC4 was < 5% during the linear phase of contraction and complete inhibition of bioconversion of LTC4 to LTD4 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 3/4 of that obtained without the inhibitor of bioconversion, the predominant response was to LTC4 itself. The spasmogenic response of the ileum to LTD4 was immediate, linear to a maximum level and immediately followed by a marked relaxation. That the failure of LTD4 to sustain a contraction was due to its immediate, rapid and quantitative conversion to the less potent LTE4 was established by pharmacologically inhibiting and anatomically deleting the converting activity. In the presence of L-cysteine, the conversion of LTD4 to LTE4 was largely inhibited and the maximum contractile response was well maintained. After anatomic removal of the mucosa that contained the LTD4 dipeptidase activity, the longitudinal smooth muscle preparation gave a maximal response to LTD4 that was fully maintained. Bioconversion is not a prerequisite for the spasmogenic activity of LTC4 and accounts for the transient response of the ileum to LTD4.