Characterization of the myelotoxicity of chloramphenicol succinate in the B6C3F1 mouse.
Chloramphenicol (CAP) is haemotoxic in man, inducing two types of toxicity. First, a dose-related, reversible anaemia with reticulocytopenia, sometimes seen in conjunction with leucopenia and thrombocytopenia; this form of toxicity develops during drug treatment. The second haemotoxicity is aplastic anaemia (AA) which is evident in the blood as severe pancytopenia. AA development is not dose-related and occurs weeks or months after treatment. We wish, in the longer term, to investigate CAP-induced AA in the busulphan-pretreated mouse. However, as a prelude to that study, we wanted to characterize in detail the reversible haemotoxicity of CAP succinate (CAPS), administered at high dose levels in the mouse, and follow the recovery of the bone marrow in the post-dosing period. Female B6C3F1 mice were gavaged with CAPS at 0, 2500 and 3500 mg/kg, daily, for 5 days and sampled (n = 5) at 1, 7, 14 and 21 days post-dosing. Blood, bone marrow and spleen samples were analysed and clonogenic assays carried out. At day 1 post-dosing, at both CAPS dose levels, decreases were seen in erythrocytes and erythrocyte precursors; marrow erythroid cells were reduced. Reductions were also evident in splenic nucleated cell counts, blood high fluorescence ratio (HFR) reticulocyte counts and total reticulocyte counts; burst-forming units-erythroid and colony-forming units-erythroid showed decreases. At day 7 post-dosing (2500 mg/kg CAPS), there was regeneration of erythrocyte production, with marked splenic erythropoietic activity, and raised blood HFR reticulocytes. At day 7, at 3500 mg/kg CAPS, erythrocyte and reticulocyte parameters remained depressed. At 14 days post-dosing (2500 mg/kg CAPS), many erythrocyte parameters had returned to normal; at 3500 mg/kg CAPS, there was erythroid regeneration. By 21 days post-dosing, at both CAPS dose levels, most erythrocytic parameters were equivalent to control values. For leucocyte parameters, there was some depression at day 1 post-dosing (at both CAPS dose levels) and signs of recovery at day 7. At days 14 and 21 post-dosing, most leucocyte parameters were close to control values. Marrow smears at day 1 post-dosing (at both CAPS dose levels) showed vacuolation of early normoblasts, of myeloid and of monocytic precursors. We conclude that the administration of CAPS at 2500 and 3500 mg/kg for 5 days induced significant myelotoxicity in female B6C3F1 mice, with cessation of erythropoiesis at day 1 post-dosing; recovery was seen over the following 7/14 days. The blood HFR reticulocyte count was a precise indicator of CAPS-induced depressive effects and subsequent recovery. It is concluded that the administration of five daily doses of CAPS at 2500 and 3500 mg/kg to the female B6C3F1 mouse induces an anaemia with reticulocytopenia, in conjunction with leucopenia, in the immediate post-dosing period; no evidence was seen at 21 days post-dosing of peripheral blood pancytopenia or a hypocellular/acellular bone marrow, which are both characteristic features of AA in man.
Turton
John A
JA
Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, London, UK. john.turton@ulsop.ac.uk
Fagg
Rajni
R
Sones
William R
WR
Williams
Thomas C
TC
Andrews
C Michael
CM
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects; D002452:Cell Count; D002701:Chloramphenicol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D012156:Reticulocytes / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects
D000900:Anti-Bacterial Agents; D002701:Chloramphenicol; C026016:chloramphenicol succinate