Nitroso-chloramphenicol: possible mediator in chloramphenicol-induced aplastic anemia.
We compared the effects of CAP and its nitroso derivative on DNA synthesis, CFU-C growth, and cell viability in human bone marrow and on mouse CFU-S viability in vitro. As previously reported from this laboratory, CAP inhibited DNA synthesis only when used in high concentrations (greater than 3 x 10(-4)M), and the inhibition was largely reversible. It also caused a reversible concentration-dependent inhibition of CFU-C growth but did not affect marrow cell viability. In sharp contrast, nitroso-CAP inhibited DNA synthesis in much lower concentrations and caused irreversible inhibition of CFU-C growth and cell death at 5 x 10(-5)M as well as irreversible mouse CFU-S damage. In a rapidly growing human lymphoid cell line, nitroso-CAP caused accumulation of cells in the G2M phase and increasing cell death within the arrested population. We have postulated from these and other observations that CAP-induced aplastic anemia occurs in the predisposed host who provides the milieu for the transformation of the p-NO2 group of the drug to toxic intermediates.
D000741:Anemia, Aplastic / Q000139:chemically induced*; D000818:Animals; D001854:Bone Marrow Cells; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D004247:DNA / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006898:Hydroxylamines / Q000633:toxicity; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D013839:Thiamphenicol / Q000633:toxicity
D006898:Hydroxylamines; D002701:Chloramphenicol; C026099:nitrosochloramphenicol; D004247:DNA; D013839:Thiamphenicol