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A Novel Mechanism for Protecting of Biomembrane from Oxidative Disorder by Oxygen Free Radicals

氧自由基保护生物膜免受氧化紊乱的新机制

基本信息

批准号：
02454488
负责人：
WATABE Tadashi
金额：
$ 4.22万
依托单位：
Tokyo College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

Lipid peroxidation induced by oxygen free radicals in animal cells on tissues has long been strongly suggested to play an important role in aging, carcinogenesis, atherosclerosis, and so on in animal and human. The purpose of this research project is to study 1) the hepatic microsomal glutathione (GSH) S-transferase (GST) protecting the microsomal membrane from disorder caused by lipid peroxidation, 2) the hepatic cytosolic GST detoxifying fatty acid hydroperoxides enzymatically released from cellular membranes, and 3) the lipid peroxide as an endogenous marker in aging. The results of these studies are summarized below.1. A small molecular size (15 KDa) of GST was isolated and purified from rat liver microsomes and identified with the previously reported microsomal protein by N-terminal amino acid sequencing. The GST directly catalyzed the reduction of various phospholipid hydroperoxides in microsomes to the corresponding alcohols in the presence of GSH. It also reduced a variety of polyunsaturated fatty acid hydroperoxides and cholesterol 7-hydroperoxides (Ch 7-OOH). The enzymatic function of this GST as a GSH peroxidase has been little known.2. A new class of homodimeric GST, designated Yrs-Yrs, was found in rat liver cytosol. The new soluble GST was isolated and purified to homogeneity from the cytosol and found to have an extremely high activity as a GSH peroxidase toward various fatty acid hydroperoxides compared with all the known GSTs. Molecular cloning of a rat liver cDNA library indicated GST Yrs-Yrs to be expressed from an unknown gene family, named theta GST, in the rat.3. In rat skin, Ch 7-OOH existing as free and ester forms accumulate with linearlity upto an age of 45 weeks after birth. The extremely good relationship (r=0.874) observed between the dermal concentration of Ch 7-OOH and aging has never been reported with any other endogenous substance. Therefore, the author proposes Ch 7-OOH in rat skin to be a new good marker in aging.

长期以来，动物细胞中氧自由基对组织的脂质过氧化作用一直被认为在动物和人类的衰老、癌症发生、动脉粥样硬化等方面起着重要作用。本研究的目的是研究1)保护肝微粒体膜免受脂质过氧化损伤的谷胱甘肽S转移酶(GST)，2)酶促肝细胞膜释放的GST解毒脂肪酸过氧化氢，3)脂质过氧化作为衰老的内源性标志物。这些研究的结果摘要如下：1.从大鼠肝微粒体中分离纯化了一个小分子量(15 KDa)的GST，并通过N-末端氨基酸序列测定，与已报道的GST蛋白进行了比较。在GSH存在下，GST直接催化微粒体内的各种磷脂过氧化氢还原成相应的醇。它还能降低多种多不饱和脂肪酸过氧化氢和胆固醇7-过氧化氢(CH7-OHO)。这种GST作为一种GSH过氧化物酶的酶功能一直知之甚少。在大鼠肝细胞浆中发现了一类新的同源二聚体GST，命名为YRS-YRS。新的可溶性GST是从胞浆中分离和纯化的，与所有已知的GST相比，它对各种脂肪酸过氧化氢具有极高的GSH过氧化物酶活性。大鼠肝脏cDNA文库的分子克隆表明，GST YRS-YRS在大鼠中表达于一个未知基因家族，命名为theta GST。在大鼠皮肤中，CH7-OHO以游离形式存在，并且在出生后45周内以线性方式积累。皮肤中CH7-OHO浓度与衰老之间存在着极好的相关性(r=0.874)，在其他内源性物质中从未见过报道。因此，作者建议将大鼠皮肤中的CH7-OHO作为一种新的良好的衰老标志物。