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Modification of DNA Bases in Chromatin of Intact Target Human Cells by Activated Human Polymorphonuclear Leukocytes¹

Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899 [M. D., R. O.]; Department of Clinical Biochemistry, Medical School, 85-094 Bydgoszcz, Poland [R. O.]; and Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California 91010 [J. H. D., S. A. A.]

We investigated whether phorbol-12-acetate-13-myristate (PMA)-activated human polymorphonuclear leukocytes (PMNs) induce base modifications in target cell DNA in vivo. Human PMNs produced 9.4 ± 0.8 (SD) nmol of H₂O₂/10⁶ cells during 50 min of exposure to 2 µg/ml PMA and 13.7 ± 2.8 nmol/10⁶ cells during exposure to PMA plus 5 mM NaN₃. Neither nonstimulated PMNs, nor PMA alone, nor NaN₃ alone induced base modifications in chromatin-associated DNA of human Ad293 cells above control levels, when assayed by gas chromatography/mass spectrometry with selected-ion monitoring. However, a 60-min exposure to 1.7 ± 0.4 x 10⁶ PMNs/ml in the presence of 2 µg/ml PMA induced a 2–3-fold increase in the level of all modified bases detected by gas chromatography/mass spectrometry with selected-ion monitoring. The guanine-derived products 8-hydroxyguanine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and the adenine-derived product 4,6-diamino-5-formamidopyrimidine were induced to the highest levels among those bases detected. These data demonstrate that exposure to activated PMNs causes DNA base modifications in target cells in vivo typical of those induced by hydroxyl radical attack. The induction of potentially promutagenic modified bases may contribute to the mutagenicity of activated PMNs.

¹ Supported by Grant CA53115 from the National Cancer Institute and by City of Hope Cancer Center Support Grant CA33572. M. D. acknowledges partial support by the Office of Health and Environmental Research, Office of Energy Research, U.S. Department of Energy, Washington, DC.

² To whom requests for reprints should be addressed, at Natl. Inst. of Stds. & Technol., Bldg. 222/A353, Gaithersburg, MD 20899.

Received 9/25/92. Accepted 1/11/93.

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