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

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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