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Metabolism of 9-ß-D-Arabinofuranosyladenine by Mouse Fibroblasts¹

Department of Microbiology, University of Colorado Medical Center, Denver, Colorado 80220

The metabolism of 9-ß-D-arabinofuranosyladenine (araA) by exponentially growing mouse fibroblasts in suspension culture has been investigated. After a 4-hr incubation with 0.1 mM [³H]araA, only 0.14% of the total ³H was in the cell fraction, whereas 48% of the araA in the medium had been deaminated to 9-ß-D-arabinofuranosylhypoxanthine. Of the cellular ³H, 80% was acid soluble, and of these 75% was associated with adenine nucleotides and 25% was associated with nucleosides. 9-ß-D-arabinofuranosylhypoxanthine comprised 80% of the labeled nucleosides, the rest being araA or adenosine. Following dephosphorylation of the acid-soluble fraction, 80% of the ³H was in araA and 9-ß-D-arabinofuranosylhypoxanthine, and 18% was in adenosine. Ninety % of the ³H in the adenine-containing triphosphates was shown to be in arabinosyl compounds, and the remainder was in adenosine and deoxyadenosine. The concentration of cellular 9-ß-D-arabinofuranosyladenine 5'-triphosphate was calculated to be 20 µM.

The RNA fraction contained 16% of the total cellular ³H. Over 90% of the ³H was associated with the adenosine 2'(3')-phosphate fraction; the remainder was nucleoside, mainly araA. When the adenosine 2'(3')-phosphate fraction was dephosphorylated, nearly 70% of the ³H was contained in adenosine, indicating extensive metabolism of araA. The remaining ³H was associated with arabinosyl compounds.

The DNA fraction contained 2% of the cellular ³H. After degradation to 5'-monophosphates, the ³H was found mainly in 9-ß-D-arabinofuranosyladenine 5'-phosphate; after dephosphorylation 95% of the ³H was in araA. Following degradation to 3'-monophosphates and terminal nucleosides, the majority of the ³H was associated with 9-ß-D-arabinofuranosyladenine 3'-phosphate, whereas a minor portion was in the nucleoside.

These results suggest that, after incubation with mouse fibroblasts, most of the exogenous araA is deaminated and remains in the medium or is otherwise metabolized. A small amount is phosphorylated to arabinosyl nucleotides that attain inhibitory cellular concentrations, and some 9-ß-D-arabinofuranosyladenine 5'-triphosphate is subsequently incorporated in internucleotide linkage into DNA.

¹ This study was supported by Grant NP-60B from the American Cancer Society, Grant 1 RO1 AI 11636-01 from the National Institute of Allergy and Infectious Diseases, and a grant from the Upjohn Company.

Received 4/24/74. Accepted 10/15/74.

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