嘌呤碱、次黄嘌呤和腺嘌呤预防6-硫代嘌呤毒性的生化基础。

Biochemical basis of the prevention of 6-thiopurine toxicity by the nucleobases, hypoxanthine and adenine.

作者信息

Hashimoto H, Kubota M, Shimizu T, Takimoto T, Kitoh T, Akiyama Y, Mikawa H

机构信息

Department of Pediatrics, Kyoto University, Japan.

出版信息

Leuk Res. 1990;14(11-12):1061-6. doi: 10.1016/0145-2126(90)90120-x.

DOI:10.1016/0145-2126(90)90120-x

PMID:2280604

Abstract

Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10 microM, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50 microM hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.

摘要

将人类白血病细胞系与天然存在的核碱基（次黄嘌呤或腺嘌呤）共同孵育可显著阻止6-硫嘌呤的细胞毒性活性。细胞外次黄嘌呤减少了6-巯基嘌呤向细胞内的转运，但腺嘌呤无显著影响。然而，当分别添加50μM次黄嘌呤或腺嘌呤时，在10μM 6-巯基嘌呤存在的情况下，细胞内硫代肌苷单磷酸的积累分别降至对照的1%以下或10%。最后，在腺嘌呤磷酸核糖转移酶缺陷型突变体中，腺嘌呤对6-硫嘌呤没有保护作用，而次黄嘌呤保留其调节活性。这些数据表明，核碱基与6-硫嘌呤竞争核糖磷酸供体5'-磷酸核糖-1-焦磷酸，从而阻止6-硫嘌呤活性代谢物的形成。