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Sister Chromatid Exchange Induced by Etheno-ATP Derivatives in Vitro¹

Departments of Biostatistics and Industrial Environmental Health Sciences, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15162

Genotoxic activities of a series of commercially purchased 1,N⁶-ethenoadenosine (-Ado) and -deoxyadenosine (-dAdo) derivatives were assessed using the sister chromatid exchange (SCE) assay in murine spleen lymphocytes in vitro. Of the -Ado adducts evaluated for SCE induction -ATP and -dATP were highly active (5x baseline) SCE inducers over a concentration range of 50–150 µM. Moderate SCE-inducing activities were seen with -dAdo, -A, and -AMP. -A was of particular interest in that spleen lymphocytes from a single mouse were highly sensitive to SCE (>50 SCE/cell at 75 µM). -Ado was weakly effective and -ADP and -dAMP did not produce significantly elevated SCEs. Cocanavalin A-stimulated T-lymphocytes and lipopolysaccharide-stimulated B-lymphocytes exhibited comparable SCE responses to -A, -AMP, and -dATP. However, B-lymphocytes were considerably less sensitive than T-lymphocytes to -dAdo and -ATP.

Evaluation of the purities of specific -Ado derivatives, as performed by high-performance liquid chromatography and thin layer chromatography, failed to detect potential contaminants as cytogenetically active agents. However, a difference (about threefold) in cytogenetic activities of two lot numbers of -ATP paralleled the difference in UV absorbance of equivalent concentrations (mg/ml), prepared according to the manufacturers stated purity. Any impurities likely to be present were consistent with inactive nonchromophoric compounds such as buffer salts.

Because of the direct genotoxic activity of -A in intact mammalian cells, we suggest that intracellular adenylate pools, including the prominent ubiquitous nucleotide ATP, are non-DNA targets for -modification by active metabolites and the resulting -adducts are likely to be active moieties in SCE induction and in neoplastic transformation produced by ethyl carbamate.

¹ This research was supported in part by Research Grant R01-CA-39401-03 awarded to M. K. C. and by BRSG 2-SOT-RR05451-27 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, NIH.

² To whom requests for reprints should be addressed, at Genetic Toxicology, University of Pittsburgh, 732 Parran Hall, School of Public Health, Pittsburgh, PA 15261.

Received 12/12/88. Revised 3/31/89. Accepted 4/11/89.