The study on the regulatory mechanism of leukotriene biosynthesis and the metabolic disturbance causing various disorders.

白三烯（Leukotrienes，LTs）是花生四烯酸衍生的一类具有生物活性的化合物，可能参与炎症和疾病的恶化。由于LT的生物活性比野牡丹素或组胺强3或4个数量级，因此这些化合物的生物合成必须高度调节。LTs的生物合成主要涉及三种酶：5-脂氧合酶、LTA_4水解酶和LTC_4合成酶。5-从小鼠肥大细胞中纯化出脂氧合酶，发现该酶可被钙离子、ATP和脂质过氧化物激活。从人白细胞和肺中分离纯化了LTA_4水解酶，该酶可将LTA_4转化为LTB_4。克隆了编码该酶的cDNA，并在细菌系统中表达，具有完整的酶活性。从豚鼠肺微粒体中溶解出LTC_4合酶，用离子交换法纯化， ...更多信息 来自先前已知的谷胱甘肽S-转移酶的酶。因此，在过去的几年里，我们的实验室已经纯化了三种重要的酶，并获得了抗体。利用这些酶的抗体，建立了酶免疫分析和组织化学研究. LT在血管痉挛发病机制中的作用。蛛网膜下腔出血后迟发性脑血管痉挛是近十年来治疗的重要靶点之一。使用实验性蛛网膜下腔出血模型，我们发现，5-脂氧合酶活性增加约20倍，血管痉挛开始前。5-动脉中的脂氧合酶在脂质过氧化物的存在下被激活。可能由不饱和脂肪酸与血红蛋白的自氧化产生的脂质过氧化物本身在脑池内注射时引起延迟型血管痉挛，并且在使用分离的基底动脉的室测定中引起严重的血管收缩。有效的脂氧合酶抑制剂与抗氧化剂的组合可以改善或预防血管痉挛。少

Leukotrienes (LTs) are a family of biologically active compounds derived from arachidonic acid, which might be involved in the inflammatory and deteriorative disorders. Since biological activities of LTs are 3 or 4 orders of magnitude more potent than prostaglandins or histamine, the biosynthesis of these compounds has to be highly regulated.1. The biosyntheses of LTs Three enzymes are mainly involved in the biosyntheses of various types of LTs; 5-lipoxygenase, LTA_4 hydrolase and LTC_4 synthase. 5-Lipoxygenase was purified from murine mast cells, and it was found that the enzyme is activated by calcium ion, ATP and lipid peroxides. LTA_4 hydrolase which converts LTA_4 to LTB_4 was purified from human leukocytes and lung. The cDNA coding for the enzyme was cloned, and was expressed in bacterial system with a full enzyme activity. LTC_4 synthase was solubilized from the microsomal fraction of the guinea pig lung; it was purified by ion exchanger which resulted in the separation of the e … More nzyme from the previously-known glutathione S-transferases. Thus, three important enzymes were purified and antibodies have become available in our laboratory in the last couple of years. By using antibodies against these enzymes, the establishment of enzymeimmunoassay and histochemical studies are ongoing.2. The role of LTs on the pathogenesis of vasospasm. The delayed type of vasospasm following subarachnoidal hemorrhage is one of the most important therapeutic target in the last decade. Using an experimental subarachnoidal hemorrhage model, we found that the 5-lipoxygenase activity was about 20-fold increased before the start of vasospasm. 5-Lipoxygenase in the artery was activated in the presence of lipid peroxides. The lipid peroxide, which is produced possibly by the autooxidation of unsaturated fatty acids with hemoglobin, itself caused the delayed- type vasospasm when injected intracisternally, and the severe vasoconstriction in the chamber assay using an isolated basilar artery. Potent inhibitors of the lipoxygenase in combination of antioxidants may improve or prevent the vasospasm. Less