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Uptake and Metabolism of Hexamethylmelamine and Pentamethylmelamine by L5178Y Lymphoblasts in Vitro¹

The Manitoba Institute of Cell Biology [A. B., J. G., G. J. G.], and the Department of Medicine, University of Manitoba [A. B., G. J. G.], Winnipeg, Manitoba, R3E 0V9, Canada

Uptake of the antitumor agents hexamethylmelamine and pentamethylmelamine by L5178Y lymphoblasts was studied using both theoretical and experimental approaches. Using the analysis of Lieb and Stein, it was predicted that, if these two drugs enter L5178Y cells by simple diffusion, uptake would be essentially complete in less than 10 sec. Experimentally, uptake of intact hexamethylmelamine and pentamethylmelamine reached a steady state within 10 sec, and the cell:medium distribution ratio for hexamethylmelamine was approximately 0.4 while that for pentamethylmelamine did not exceed 0.1. Additional evidence that uptake of both drugs was by simple diffusion was that uptake of intact hexamethylmelamine and pentamethylmelamine showed little temperature dependence and was not inhibited by a variety of metabolic inhibitors.

Metabolism of hexamethylmelamine and pentamethylmelamine was studied using thin-layer chromatographic analysis of cell contents. Cells treated with methyl-labeled hexamethylmelamine and pentamethylmelamine showed a more prominent radioactive fraction at the origin than did cells treated with the corresponding ring-labeled drugs. In cells treated with ring-labeled hexamethylmelamine or pentamethylmelamine, greater than 95% of the origin fraction was exchangeable, suggesting that this fraction consists primarily of demethylated polar metabolites. With either methyl-labeled drug, greater than 75% of the origin fraction was ethanol soluble and exchangeable, suggesting the presence of one or more polar metabolites not containing the melamine ring.

Pentamethylmelamine was detected within 1 min in cells treated with hexamethylmelamine; the cell:medium ratio for pentamethylmelamine under these conditions was 19-fold greater than that observed when pentamethylmelamine influx alone was being studied. These findings provide direct evidence for the formation of pentamethylmelamine by metabolism from hexamethylmelamine in L5178Y cells.

¹ This work was supported by a grant from the National Cancer Institute of Canada.

Received 6/ 4/80. Accepted 7/25/80.