Aerobic nitroreduction of dehydrochloramphenicol by bone marrow.
It has been previously demonstrated that dehydrochloramphenicol (DH-CAP), a bacterial metabolite of chloramphenicol, induces DNA single strand breaks in intact cells and is profoundly more cytotoxic than chloramphenicol (CAP). In view of previous observations relating genotoxicity of nitrocompounds to their nitroreduction by the target tissue, we studied the nitroreduction of DH-CAP by human and rabbit bone marrow. Nitroreduction by tissue homogenates was determined by the Bratton Marshall colorimetric assay and by high-performance liquid chromatography (HPLC). Nitroreduction of DH-CAP by bone marrow cell homogenates was observed under aerobic conditions and the reduction was both cell concentration- and time-dependent. The formation of the amino product aminodehydrochloramphenicol was confirmed by HPLC. Reduction by other tissues including human liver, Raji cells, and HL-60 tumors was also observed. These results suggest that genotoxicity of DH-CAP may be related to its nitroreduction by the target tissue with in situ production of toxic intermediates. Together with previous studies, these observations lend support to the thesis that the p-NO2 group may be the structural feature underlying aplastic anemia from CAP.
Isildar
M
M
Department of Medicine, University of Miami, School of Medicine, Florida 33101.
Abou-Khalil
W H
WH
Jimenez
J J
JJ
Abou-Khalil
S
S
Yunis
A A
AA
D000332:Aerobiosis; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects; D006801:Humans; D009574:Nitro Compounds / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
D009574:Nitro Compounds; C056132:dehydrochloramphenicol; D002701:Chloramphenicol; D004247:DNA