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.
Ambekar
C S
CS
Department of Medicine, The University of Hong Kong, Hong Kong. ambekar@net-yan.com
Lee
J S K
JS
Cheung
B M Y
BM
Chan
L C
LC
Liang
R
R
Kumana
C R
CR
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000502:physiology; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology* / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011500:Protein Synthesis Inhibitors / Q000032:analysis; D051381:Rats; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
D011500:Protein Synthesis Inhibitors; D002701:Chloramphenicol; D013385:Succinate Dehydrogenase; C026016:chloramphenicol succinate