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Enzymatic Activation of the Oncogen 3-Hydroxyxanthine¹

Division of Biological Chemistry, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

The oncogen 3-hydroxyxanthine is enzymatically converted to a chemically reactive form by a protein fraction of the 100,000 x g supernatant of rat liver. The activated derivative reacts in vitro with free or protein-bound methionine, and the assay of the activation is based on the amount of 8-methylmercaptoxanthine formed; 3-hydroxyguanine yields 8-methylmercaptoguanine in this system. The cofactor requirements suggest that the activated intermediate is the 3-O-ester derived from 3-hydroxyxanthine and sulfuric acid. With cofactors favoring phosphate transfer, extensive activation is observed, but the participation of catalytic amounts of sulfate could not be excluded. Experiments with glucuronate or acetate transferring systems were inconclusive. 8-Methylmercaptoxanthine is not altered by the enzyme preparation, although the intact rat metabolized about 10% of it to a product which may be 8-methylsulfinylxanthine.

¹ This investigation was supported in part by National Cancer Institute Grant CA 08748, and American Cancer Society Grant P-295. This is paper 42 of a series on "Purine N-Oxides." Portions were presented at the 61st Annual Meeting of the American Association for Cancer Research, Philadelphia, in April, 1970 (Proc. Am. Assoc. Cancer Res., 11: 76, 1970), and at the Tenth International Cancer Congress, Houston (Abstracts, 1970, p. 8).

Received 9/28/71. Accepted 12/ 9/71.

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