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Development of inhibitor for 20a-hydroxysteroid dehydrogenase

20α-羟基类固醇脱氢酶抑制剂的开发

基本信息

批准号：
05556052
负责人：
SHIOTA Kunio
金额：
$ 10.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

项目摘要

20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) is an enzyme which catalizes progesterone to a biologically inactive steroid 20alpha-dihydroprogesterone (4-pregnen-20a-ol-3-one : 20alpha-OHP). The activity of this enzyme is found to be distributed in endocrine tissues including the ovary, testis, placenta and adrenal gland. Since progesterone is the precursor of biologically active steroids such as an androgen, estrogen, and corticoid, an increase in this enzyme may alter the regulation of their secretion. 20alpha-HSD is also distributed in a variety of tisuues including T-cells, Macrophage and erthrocytes. Interestingly, enzyme activity is found in spontaneous neoplasms of animals. 20alpha-HSD activity was found in the tissue surrounding the fetus during pregnancy in the rat except for the specific period during which spontaneous fetus loss occurs. Although physiological or pathological role role of 20alpha-HSD has not been determined, it is clear that the enzyme plays a role other than the regulation of steroid secretion and 20alpha-HSD mat be important in may biological process including cytodifferentiation and survival of the cells. To clarify these problems, development of specific inhibitors for 20alpha-HSD has been needed and various steroid derivatives have screened. In the series of the experiment, the derivatives @92STZ-26 is selsected as 20alpha-HSD.This derivative is effective to inhibit purified 20alpha-HSD activity under the invitro condition and in vivo condition.

20α-羟基类固醇脱氢酶(20α-HSD)是一种催化孕酮生成生物活性不活跃的类固醇20α-二氢孕酮(4-孕烯-20a-醇-3-酮：20α-OHP)的酶。这种酶的活性分布在内分泌组织中，包括卵巢、睾丸、胎盘和肾上腺。由于孕酮是生物活性类固醇的前体，如雄激素、雌激素和皮质醇，这种酶的增加可能会改变它们的分泌调节。20α-HSD也分布在多种组织中，包括T细胞、巨噬细胞和红细胞。有趣的是，在动物的自发肿瘤中发现了酶的活性。20Alpha-HSD活性在大鼠妊娠期间胎儿周围组织中发现，但在发生自发性流产的特定时期除外。虽然20α-HSD的生理或病理作用尚未确定，但很明显，该酶在调节类固醇分泌之外还发挥着作用，20α-HSD可能在细胞分化和细胞存活等生物学过程中发挥重要作用。为了阐明这些问题，需要开发20α-HSD的特异性抑制剂，并筛选各种类固醇衍生物。在一系列实验中，我们选择了@92STZ-26的衍生物作为20α-HSD，该衍生物在体内外条件下都能有效地抑制纯化的20α-HSD的活性。