Effects of antioxidants and a caspase inhibitor on chioramphenicol-induced toxicity of human bone marrow and HL-60 cells

Abstract

Chloramphenicol (CAP), a board spectrum antibiotic widely used in many developing countries, has toxic side effects on bone marrow, the most serious of which is aplastic anemia. Recent studies suggest that effects of CAP on suppressing hematopoietic colony formation may be abrogated by antioxidants. In addition, there is preliminary evidence that CAP induces apoptosis in hemopoietic stem cells, leading to aplastic anemia. We have been unable to demonstrate the protective effects of a variety ofantioxidants on CAP-induced suppression of burst-forming unit erythroid (BFU-E) and colony-forming unit granulocyte/ monocyte (CFUGM). Using flow cytometry, we have, however, confirmed that CAP can induce apoptosis in purified human bone marrow CD34 + cells. We also showed that a caspase inhibitor, Z-VAD.fmk, can ameliorate the apoptotic-inducing effects of CAP in the HL-60 cell line.

Keywords

chloramphenicol aplastic anemia CD34 antioxidant apoptosis

References

1 Ehrlich J , et al. Chloromycetin, a new antibiotic from a soil actinomycete . Science. 1947; 106: 417-419 .

2 Kapusnik-Uner JE , Sande MA , Chambers HF. Antimicrobial agents. Tetracyclines, chloramphenicol, erythromycin, and miscellaneous antibacterial agents. In: Hardman JG , Limbird LE , Molinoff PB , Ruddon RW , Gilman AG (eds.), Goodman's and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. McGraw-Hill , 1996.

3 Volini UF , et al. Hematopoietic changes during administration of chloramphenicol . JAMvA, J Am Med Assoc. 1950; 142: 1333-1333 .

4 Oliwenstein L. Meningitis in Africa: 15,000 die. Discover January 90, 1997.

5 Buckley SA. Survey of patients taking topical medication at their first presentation to eye casualty . Br Med J. 1990; 311: 451-451 .

6 Martelo OJ , Manyan DR , Smith US , Yunis AA. Chloramphenicol and bone marrow mitochondria . J Lab Clin Med. 1969; 74: 927-942 .

7 Kroemer G , Zamzami N , Susin SA. Mitochondrial control of apoptosis . Immunol Today. 1997; 18: 44-51 .

8 Holt DE , et al. The myelotoxicity of chloramphenicol: in vtro and in vivo studies: I. In vitro effects on cells in culture . Hum Exp Toxicol. 1997; 16: 570-576 .

9 Callera F , Garcia AB , Falcao RP. Fas-mediated apoptosis with normal expression of bcl-2 and p53 in lymphocytes from aplastic anemia . Br J Hematol. 1998; 100: 698-703 .

10.

10 Philpott NJ , et al. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance . Exp Hematol. 1995; 23: 1642-1648 .

11.

11 Kumar S , Harvey NL. Role of multiple cellular proteases in the execution of programmed cell death . FEBS Lett. 1995; 375: 169-173 .

12.

12 Thornberry NA , Molineaux SM. Interleukin-beta converting enzyme: a novel cysteine protease required for IL1 beta production and implicated in programmed cell death . Protein Sci. 1995; 4: 3-12 .

13.

13 Yunis AA , Adamson JW. Differential in vitro sensitivity of marrow erythroid and granulocytic colony forming cells to chloramphenicol . Am J Hematol. 1977; 2: 355-363 .

14.

14 Stocker R , Frei B. Endogenous antioxidant defences in human blood plasma. In: Sies H (ed.), Oxidative Stress: Oxidants and Antioxidants. Academic Press, London , 1991, pp. 213-242.

15.

15 Holt DE. PhD Thesis, University of London, 1992.

16.

16 Yunis AA , et al. Nitroso-chloramphenicol: possible mediator in chloramphenicol-induced aplastic anemia . lLab Clin Med. 1980; 96: 36-46 .

17.

17 Jimenez JJ , Arimura GK , Abou-Khalil WH , Isildar M , Yunis AA. Chloramphenicol-induced bone marrow injury: possible role of bacterial metabolites of chloramphenicol . Blood. 1987; 70: 1180-1185 .

18.

18 Isildar M , Jimenez JJ , Arimura GK , Yunis AA. DNA damage in intact cells induced by bacterial metabolites of chloramphenicol . Am J Hematol. 1988; 28: 40-46 .