Chloramphenicol succinate, a competitive substrate and inhibitor of succinate dehydrogenase: possible reason for its toxicity.

From our previous study [Eur. J. Clin. Pharmacol. 56 (2000) 405] we hypothesized that chloramphenicol succinate (CAPS) may be a competitive substrate for succinate dehydrogenase (SDH). It may be oxidized by SDH to release chloramphenicol (CAP), which may inhibit SDH by feed back mechanism. The present ex-vivo/in vitro study was aimed to investigate this possibility by using human tissues (bone marrow and liver samples) and animal tissues (rat liver and kidney). The effect of different SDH activators and specific inhibitors was studied on CAPS metabolism by SDH. The metabolites and reduction products were detected by using HPLC. In marrow samples, CAPS was slowly oxidized to form CAP. The formation of CAP (oxidation product) was enhanced by FAD and low malonate and inhibited by high malonate and 3-NPA. Similar results were obtained with mitochondria from human and rat tissues. These studies suggest that CAPS could be a competitive oxidative substrate and the metabolite CAP could be an inhibitor at the reduction site. Therefore, SDH could be a target molecule responsible for CAPS induced toxicity.

Metabolism of chloramphenicol succinate in human bone marrow.

OBJECTIVE/METHODS: The metabolism of chloramphenicol succinate (CAPS) by human bone marrow was studied in vitro using 75 marrow samples. Whole marrow samples were incubated with CAPS with or without reduced nicotinamide adenine dinucleotide phosphate for 1, 2 and 3 h at 37 degrees C. Ficoll-paque-separated marrow mononuclear cells and erythrocytes were similarly incubated. After precipitation and centrifugation, clear supernatant was analysed for the presence of metabolites using high-performance liquid chromatography. RESULTS: Only one metabolite was detected when CAPS was incubated for 3 h with whole marrow from 72 donors. Its retention time (RT 10.9 min) corresponded to chloramphenicol (CAP). When CAPS was incubated with samples of whole marrow, marrow mononuclear cells, marrow erythrocytes, marrow plasma and peripheral blood from one donor who had taken Traditional Chinese Medicine (TCM), three metabolite peaks were detected within 15 min to 1 h. The RT of two of these peaks corresponded to CAP and nitroso-CAP (RT 14.9 min), but one peak remained unidentified. These peaks were not detected in the control samples incubated without CAPS. Blood samples collected after 3 months and 6 months to reconfirm metabolic activity yielded no such metabolite peaks when incubated with CAPS for 1-3 h. Therefore induction of enzyme activity by TCM was suspected. Three metabolite peaks with the same RTs were also detected when CAPS was incubated for 3 h with whole marrow from two other donors. CONCLUSION: These studies demonstrated that CAPS may be metabolised to CAP and occasionally other metabolites in human bone marrow. This novel observation is particularly important because the bone marrow is known to be a target organ for chloramphenicol toxicity.