Degradation of isolated deoxyribonucleic acid mediated by nitroso-chloramphenicol. Possible role in chloramphenicol-induced aplastic anemia

Thomas Murray, Kathleen M. Downey, Adel A. Yunis

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Abstract

Reduction of the nitro group of chloramphenicol (CAP) gives rise to more highly reactive intermediates which may be involved in the aplastic anemia associated with CAP use. One such intermediate, nitroso-chloramphenicol (NO-CAP), has been found to be a potent agent for mediating degradation of isolated DNA. In a reaction mixture containing 100 μM NO-CAP, 100 μM CuCl2, and 5 mM NADH, 7 μg of Escherichia coli [3H]DNA was completely degraded to acid-soluble fragments in 30 min. Damage to DNA was in the form of single-stranded scissions. The requirement for copper was specific, and copper chelating reagents blocked the degradation. The need for a reducing agent could be met equally well by NADH or NADPH, but not by sulfhydryl reagents such as glutathione, dithiothreitol and 2-mercaptoethanol. Oxygen was also necessary for the NO-CAP-mediated DNA damage, with reduced forms of oxygen participating in the reaction. A role for H2O2 was indicated by the inhibition of the degradation seen when catalase was included in the mixture. Hydroxyl radicals are known to be produced in the reaction of H2O2 with certain transition metals. Scavangers of hydroxyl radicals also inhibited strand-scission, suggesting that the radicals may be the primary agents in DNA degradation. The importance of the nitroso moiety of NO-CAP was evidenced by the lack of DNA damage seen when NO-CAP was replaced by CAP under the conditions tested.

Original languageEnglish (US)
Pages (from-to)2291-2296
Number of pages6
JournalBiochemical Pharmacology
Volume31
Issue number13
DOIs
StatePublished - Jul 1 1982

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ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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