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Formation and Significance of 6-Methylthiopurine Ribonucleotide as a Metabolite of 6-Mercaptopurine¹

Kettering-Meyer Laboratories, Southern Research Institute,² Birmingham, Alabama 35205

6-Methylthiopurine (6-MeMP) ribonucleotide was identified as a metabolite of 6-mercaptopurine (6-MP) or of 6-MP ribonucleoside in cultured L1210 leukemia cells, adenocarcinoma 755 cells, and H. Ep. No. 2 cells; in ascitic L1210 cells and adenocarcinoma 755 cells in vivo; and in solid adenocarcinoma 755 and liver of host mice. The extent of conversion of 6-MP and 6-MP ribonucleoside to 6-MeMP ribonucleotide varied markedly among the cells studied. The methyl derivative apparently was formed by the pathway 6-MP 6-MP ribonucleotide 6-MeMP ribonucleotide. The amounts of 6-MeMP ribonucleotide formed and the much greater efficiency of 6-MeMP ribonucleotide than 6-MP ribonucleotide as an inhibitor of phosphoribosyl pyrophosphate amidotransferase make it likely that 6-MeMP ribonucleotide is responsible for most or all of the inhibition of de novo purine synthesis produced by 6-MP.

6-MP, 6-MP ribonucleoside, and 6-MP ribonucleotide were each methylated in vitro by a nonenzymatic transfer of the methyl group from S-adenosylmethionine. A line of H. Ep. No. 2 cells resistant to 6-MP because of lack of hypoxanthine phosphoribosyltransferase and hence unable to convert 6-MP to 6-MP ribonucleotide was used to determine that the following pathway was operative: 6-MP ribonucleoside 6-MeMP ribonucleoside 6-MeMP ribonucleotide. The conversion was barely detectable in untreated cells but was increased severalfold in the presence of high concentrations of hypoxanthine or inosine, which presumably inhibited or saturated the phosphorylase and thus prevented the cleaving of 6-MP ribonucleoside to 6-MP.

¹ This work was supported by Grant T-13K from the American Cancer Society; Contract PH43-66-29 with Chemotherapy, National Cancer Institute, NIH; and grants from the C. F. Kettering Foundation and the Alfred P. Sloan Foundation.

² Affiliated with the Sloan-Kettering Institute for Cancer Research, New York, N. Y.

Received 8/12/70. Accepted 9/29/70.