Biochemical basis of the prevention of 6-thiopurine toxicity by the nucleobases, hypoxanthine and adenine |
| |
Authors: | Hisako Hashimoto Masaru Kubota Tsunehiro Shimizu Tetsuya Takimoto Toshiyuki Kitoh Yuichi Akiyama Haruki Mikawa |
| |
Affiliation: | Department of Pediatrics, Kyoto University, Japan. |
| |
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. |
| |
Keywords: | 6-Thiopurine hypoxanthine, adenine, transport, phosphoribosylation |
本文献已被 ScienceDirect 等数据库收录! |
|