Add time:08/19/2019         Source:sciencedirect.com

The disposition of S-(6-purinyl)glutathione (6-PG) and its metabolites, including the antitumor agent 6-mercaptopurine (6-MP), was characterized in freshly isolated renal cortical cells from male F344 rats to assess the ability of the kidney to convert 6-PG to 6-MP. The intracellular transport and accumulation of 6-PG and 6-MP, the metabolism of 6-PG to 6-MP, and the potential cytotoxicity of 6-MP, 6-thioxanthine (6-ThXan), and 6-thioguanine (6-ThGua) were determined. 6-PG and 6-MP were accumulated by renal cortical cells by time- and concentration-dependent processes, reaching maximal levels of 14.2 and 1.52 nmol/106 cells, respectively, with 1 mM concentrations of each compound. Treatment with acivicin, an inhibitor of 6-PG metabolism by γ-glutamyltransferase, increased accumulation of 6-PG, and treatment with α-keto-γ-methiolbutyrate, a keto acid cosubstrate that stimulates activity of the cysteine conjugate β-lyase (β-lyase), which generates 6-MP, decreased accumulation of 6-PG. Incubation of renal cells with 10 mM 6-PG generated 6-MP at a rate of 2.4 nmol/min per 106 cells, demonstrating that the β-lyase pathway forms the desired product from the prodrug within the intact renal cell. Preincubation of cells with acivicin or aminooxyacetic acid, an inhibitor of the β-lyase, decreased the net formation of 6-MP, demonstrating further the function of the β-lyase. 6-MP, 6-ThXan, and 6-ThGua exhibited approximately equivalent cytotoxicity (45–55% release of lactate dehydrogenase with 1 mM at 2 hr) in isolated renal cells. Based on the known antitumor potency of these agents, this suggests that cytotoxicity and antitumor activity occur by distinct mechanisms. The high amount of accumulation of 6-PG and its subsequent metabolism to 6-MP, as compared with the relatively low amount of accumulation of 6-MP, in renal cells suggest that 6-PG can function as a prodrug and is a more effective delivery vehicle for 6-MP to renal cells than 6-MP itself. Administration of 6-PG may be an effective means of treating renal tumors or suppressing renal transplant rejection.

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