Biochemical Studies on the Putative Nitroso Metabolite of Chloramphenicol: A New Model for the Cause of Aplastic Anemia

Abstract

Chloramphenicol (CAP) is one of the oldest and more potent broad spectrum antibiotics available for the treatment of certain severe infections. CAP is an unusual natural product since it possesses both the nitro functional group and C-Cl bonds, neither of which are particularly common among terrestrial natural products. The necessity of the nitro functional group to the antimicrobial action of CAP has been thoroughly studied (reviewed in ref. 1). Unfortunately, the clinical use of CAP often causes toxic reactions, most notably to the hemopoietic system (2). The most serious of these actions is the rare, but generally fatal condition of aplastic anemia (hypoplastic marrow failure). In 1980 Tunis made the hypothesis that reduced intermediates (nitroso, hydroxylamine) of the nitro group of CAP were responsible for the aplastic anemia associated with CAP (2); however, this hypothesis had actually been proposed by the Weisburgers in 1967 (3). It was the Weisburgers’ hypothesis that prompted us to synthesize CAP-NO, CAP-NHOH and related analogs in 1978 (1), and to investigate the potential toxicity of such putative metabolites to hemopoietic precursor cells (4,5).