DEGRADATION OF 2-(3-AMINOPROPYLAMINO)ETHANETHIOL (WR-1065) BY CU-DEPENDENT AMINE OXIDASES AND INFLUENCE ON GLUTATHIONE STATUS OF CHINESE-HAMSTER OVARY CELLS
DEGRADATION OF 2-(3-AMINOPROPYLAMINO)ETHANETHIOL (WR-1065) BY CU-DEPENDENT AMINE OXIDASES AND INFLUENCE ON GLUTATHIONE STATUS OF CHINESE-HAMSTER OVARY CELLS
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DOI：
10.1016/0006-2952(95)00164-u
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发表时间：
1995-08-08
影响因子：
5.8
通讯作者：
ISSELS, RD
中科院分区：
文献类型：
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作者：
MEIER, T;ISSELS, RD
放射防护剂2-(3-氨基丙氨基)乙硫醇(WR-1065)在体外细胞培养液中可被降解。降解反应消耗氧气，并且是存在于介质的血清内容物中的铜依赖的胺氧化酶作用的结果。对WR-1065降解产物的分析表明，降解产物中含有半胱胺、丙烯醛和过氧化氢。WR-2721是WR-1065的失活前体药物，不是这些酶的底物。依赖铜的胺氧化酶胞外降解WR-1065导致中国仓鼠卵巢(CHO)细胞内谷胱甘肽(GSH)的耗竭，并降低克隆形成细胞的存活率。氨基胍是一种铜依赖的胺氧化酶的抑制剂，它的加入可以保护CHO细胞免受WR-1065的毒性作用，在这种情况下，细胞内GSH水平会增加。这些数据表明，WR-1065可以在铜依赖的胺氧化酶的存在下被降解为有毒化合物，这可能对WR-2721的临床应用有进一步的意义。
The radioprotective drug 2-(3-aminopropylamino) ethanethiol (WR-1065) can be degraded when incubated in cell culture medium in vitro. The degradation reaction consumes oxygen and results from the action of Cu-dependent amine oxidases present in the serum content of the medium. Analysis of the degradation products of WR-1065 demonstrates the formation of cysteamine, acrolein and H2O2. WR-2721, the inactive prodrug of WR-1065, is not a substrate for these enzymes. Extracellular degradation of WR-1065 by Cu-dependent amine oxidases leads to an intracellular depletion of glutathione (GSH) in Chinese hamster ovary (CHO) cells and to reduction of clonogenic cell survival. Addition of aminoguanidine, an inhibitor of Cu-dependent amine oxidases, protects CHO cells from the toxic effects of WR-1065 and under these conditions an increase of intracellular GSH levels occurs. These data demonstrate that WR-1065 can be degraded to toxic compounds by the presence of Cu-dependent amine oxidases which might have further implications for the clinical use of WR-2721.