Analysis of leukotrene C4 synthase in allergic diseases in childhood

白三烯C4被认为是包括支气管哮喘在内的过敏性疾病发病机制中最重要的介质之一。最近，已经证明LT的合成酶的活性是由遗传决定的。我们研究了在LTC 4合酶的启动子区域（翻译起始位点上游~ 444 bp）中A-C转换的普遍性。过敏性疾病中C/C型占10%，A/C型占60%。对照组C/C型占0%，A/C型占27.3%。这些结果支持了LTC 4合酶启动子区的A-C转换与LTC 4合酶活性相关的可能性。这些结果也表明，LTC 4合酶活性的调节可能有助于过敏性疾病，包括支气管哮喘的发病机制。我们还使用肥大细胞衍生的培养细胞（RBL ;大鼠嗜碱性白血病）研究了多种化学物质对LT合成的抑制作用，发现（9- [4-乙酰基-3-羟基-2-正丙基苯氧基甲基]-3（1H-四唑-5-基）-4H-吡啶并[1，2-a]嘧啶-4-酮）AS-35是LT合成酶活性的有效抑制剂。在支气管哮喘患者中，LT合成的两个关键酶5-脂氧合酶和LTC 4合成酶在转录水平上调。这些结果表明，LTC 4合酶和5-脂氧合酶的转录调控在儿童过敏性疾病的发病机制中起着重要作用。

It has been considered that leukotriene(LT)C4 is one of the most important mediators in the pathogenesis of allergic diseases including bronchial asthma. Recently, it has been demonstrated that the activities of synthesizing enzymes of LTs are genetically determined. We investigated the prevalence of A-C conversion in the promoter region of LTC4 synthase (-444bp up-stream from the initiation site of translation). Ten percents of patients with allergic diseases were C/C type and 60 % of patients were A/C type. On the other hands , the control subjects with C/C type were 0 % and those with A/C type were 27.3 %. These results supported a possibility that A-C conversion of LTC4 synthase in the promoter region was associated with the enzyme activity of LTC4 synthase. These results also indicate that the regulation of LTC4 synthase activity may contribute the pathogenesis of allergic diseases including bronchial asthma. We also investigated the inhibitory action of a variety of chemical substances on LT-synthesis using mast cell derived cultured cells (RBL ; rat basophilic leukemia) and found that (9- [4-acetyl-3-hydroxy-2-n-propylphenoxy methyl]-3 (1H-tetrazol-5-yl)-4H-pyrido[1,2-a] pyritnidin-4-one) ; AS-35, was potent inhibitor of LT synthase activity. In the patients with bronchial asthma, 5-lipoxygenase and LTC4 synthase, two pivotal enzymes of LT-synthesis, were up-regulated at the transcriptional level. These findings indicate that the transcriptional regulation of LTC4 synthase and 5-lipoxygenase plays an important role in the pathogenesis of allergic diseases in child hood.