The reactivity of chloramphenicol reduction products with DNA bases

The interaction between the constituent bases of deoxyribonucleic acid and the reduction products of the nitro-aromatic compound chloramphenicol and its nitroso derivative have been studied using an electrochemical system.

The changes to the voltammetry of chloramphenicol and nitrosochloramphenicol upon addition of adenine, cytosine, guanine, and thymine at various concentrations have been measured. The biological implications of reductive activation of both chloramphenicol and nitrosochloramphenicol were examined using a phi X174 double transfection technique which measures biologically relevant deoxyribonucleic acid damage.

Measurement of the voltammetric response of chloramphenicol shows that the most noticeable change upon base addition is a decrease in the lifetime of the nitro radical anion in the following order of decreasing activity: adenine, thymine, and cytosine. No effect was observed with guanine. The reversible 2-electron nitrosochloramphenicol-hydroxychloramphenicol couple showed no interaction on the voltammetric timescale, although binding of the hydroxylamine to guanine was observed. Interaction of the azo derivative, formed as a consequence of further reduction plus chemical reaction of nitrosochloramphenicol was observed. Biological studies showed that no significant effect on deoxyribonucleic acid by chloramphenicol or nitrosochloramphenicol was observed under oxic conditions. Controlled reduction of nitrosochloramphenicol to the hydroxylamine gave considerably less damage than when nitrosochloramphenicol or chloramphenicol was completely reduced.

The chloramphenicol nitro radical anion reacts selectively with the bases of deoxyribonucleic acid. Reduction products of nitrosochloramphenicol beyond the 2-electron hydroxylamine are highly reactive to deoxyribonucleic acid.