Chloramphenicol-induced bone marrow injury: possible role of bacterial metabolites of chloramphenicol

Abstract

To explore the potential role of some bacterial metabolites of chloramphenicol (CAP) in CAP-induced hematotoxicity, we examined their cytotoxic effects on bone marrow cells in vitro using a number of cytotoxicity parameters. Among the metabolites tested, dehydro-CAP (DHCAP) and p-nitrophenyl-2-amino-3 hydroxypropanone-HCI (NPAP) were more toxic than CAP. DHCAP was at least as toxic as nitroso-CAP. At concentrations of less than or equal to 10(-4) mol/L, DHCAP caused total irreversible inhibition of myeloid colony (CFU-GM) growth and 80% inhibition of DNA synthesis in human bone marrow. Incubation of human bone marrow cells with 10(-4) mol/L nitroso-CAP or DHCAP for 24 hours resulted in 75% and 65% cell death respectively. Although DHCAP was 10- to 20-fold more cytotoxic than CAP, it was only one third as effective in inhibiting mitochondrial protein synthesis, indicating that DHCAP exerts its toxic effect by alternate mechanisms. The cytotoxicity of DHCAP and its relative stability, compared to the unstable nitroso CAP, suggest that this bacterial metabolite of CAP, and possibly others, may play a significant role in CAP-induced hematotoxicity.

Challenges with linezolid therapy and reversible pancytopenia

“…In addition, both act to inhibit protein synthesis at the ribosomal level. There is well-established evidence that reversible bone marrow suppression from chloramphenicol toxicity occurs from mitochondrial injury [4,5]. The chloramphenicol concept for myelosuppression proved to be an excellent framework to study new potential myelotoxins.…”

A Case of Aplastic Anemia Associated With Long-Term Metronidazole Use

“…Notably, chloramphenicol (CAP) is the only other antimicrobial known to cause this degree of hematologic dyscrasia. 9 While the cause of aplastic anemia related to CAP is well described in the literature, the exact pathogenesis of metronidazole-induced hematologic dyscrasias is not well understood. Animal studies have revealed that metronidazole use results in fragmentation and breaks in the chromosomes of bone marrow cells.…”

Scientific Opinion on Chloramphenicol in food and feed

“…The CONTAM Panel noted that these two papers reported a structure suggesting that HCl is covalently bound to the aminogroup of dehydro-CAP base. These metabolites have been implicated in the haematotoxicity of the antibiotic (Jimenez et al, 1987;Robbana-Barnat et al, 1997) and have been tested for their effects on DNA using the alkaline elution assay (Isildar et al, 1988b;Lafarge-Frayssinet et al, 1994) (see Section 7.2.7).…”

“…from tissue or gastro-enteric bacteria), are still a matter of debate or are simply not known. Compared with other metabolites, nitroso-chloramphenicol, dehydro-chloramphenicol and, to a lesser extent, dehydrochloramphenicol base and NPAP are characterised by higher cyto-and genotoxic potency (Lafarge-Fraissinet et al, 1994, Jimenez et al, 1987Isildar et al, 1988b;Robbana-Barnat et al, 1997). The presence of all such metabolites except dehydro-chloramphenicol base has been demonstrated in kidney, liver and muscle samples from broiler chickens orally administered 50 mg chloramphenicol/kg b.w.…”