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Conference Paper: Chloramphenicol succinate a competitive substrate and inhibitor of succinate dehydrogenase: relation to its mechanisms of toxicity

TitleChloramphenicol succinate a competitive substrate and inhibitor of succinate dehydrogenase: relation to its mechanisms of toxicity
Authors
Issue Date2003
PublisherHong Kong Medical Association. The Journal's web site is located at http://www.hkmj.org
Citation
The 8th Medical Research Conference of Department of Medicine, The University of Hong Kong, Hong Kong, 25 – 26 January 2003. In Hong Kong Medical Journal, 2003, v. 9 n. S1, p. 64 How to Cite?
AbstractObjective/Method: Chloramphenicol succinate (CAPS) causes marrow depression and in some cases severe aplastic anaemia. Molecular mechanism of this toxicity is still unknown. We studied Ex-vivo metabolism of this antibiotic by human bone marrow to investigate how it is metabolized and which enzyme is involved. To study metabolism marrow samples were incubated with CAPS. To investigate involvement of succinate dehydrogenase (SDH) in CAPS metabolism, marrow samples and rat liver mitochondria were incubated with CAPS in the presence and absence of a known SDH activators and inhibitors at 370 C. Detection of metabolites was carried out by HPLC. Results: In 72 marrow samples, CAPS was slowly metabolized to chloramphenicol (CAP). In 20 marrow samples, flavin adenine dinucleotide (FAD) enhanced CAP formation but reduction of FAD to FADH2 was inhibited. While in 3 samples it was metabolized to CAP, nitroso-CAP and another metabolite. Marrow incubated with FAD (control) showed FADH2 peak. No CAP formation was observed when marrow and CAPS were incubated with malonate and 3-NPA. Mitochondria metabolized CAPS to CAP. FAD, succinate and malonate enhanced CAP formation but reduction of FADH2 was inhibited. While, oxaloacetate, 3-NPA and nitroso-CAP inhibited CAPS metabolism to CAP. Conclusions: These studies demonstrate that CAPS is a competitive substrate for SDH. In marrow and mitochondria, it is oxidized to CAP by SDH and nitro metabolites formed may be responsible for inhibition of SDH. In some marrows presence of SDH isoenzyme may be responsible for both oxidation and nitroreduction of CAPS to CAP, nitroso-CAP and possibly hydroxylamino-CAP. SDH may be a target for CAPS induced marrow toxicity.
Persistent Identifierhttp://hdl.handle.net/10722/101969
ISSN
2015 Impact Factor: 0.887
2015 SCImago Journal Rankings: 0.279

 

DC FieldValueLanguage
dc.contributor.authorAmbekar, CSen_HK
dc.contributor.authorKumana, CRen_HK
dc.contributor.authorLiang, RHSen_HK
dc.contributor.authorCheung, BMYen_HK
dc.date.accessioned2010-09-25T20:11:47Z-
dc.date.available2010-09-25T20:11:47Z-
dc.date.issued2003en_HK
dc.identifier.citationThe 8th Medical Research Conference of Department of Medicine, The University of Hong Kong, Hong Kong, 25 – 26 January 2003. In Hong Kong Medical Journal, 2003, v. 9 n. S1, p. 64en_HK
dc.identifier.issn1024-2708-
dc.identifier.urihttp://hdl.handle.net/10722/101969-
dc.description.abstractObjective/Method: Chloramphenicol succinate (CAPS) causes marrow depression and in some cases severe aplastic anaemia. Molecular mechanism of this toxicity is still unknown. We studied Ex-vivo metabolism of this antibiotic by human bone marrow to investigate how it is metabolized and which enzyme is involved. To study metabolism marrow samples were incubated with CAPS. To investigate involvement of succinate dehydrogenase (SDH) in CAPS metabolism, marrow samples and rat liver mitochondria were incubated with CAPS in the presence and absence of a known SDH activators and inhibitors at 370 C. Detection of metabolites was carried out by HPLC. Results: In 72 marrow samples, CAPS was slowly metabolized to chloramphenicol (CAP). In 20 marrow samples, flavin adenine dinucleotide (FAD) enhanced CAP formation but reduction of FAD to FADH2 was inhibited. While in 3 samples it was metabolized to CAP, nitroso-CAP and another metabolite. Marrow incubated with FAD (control) showed FADH2 peak. No CAP formation was observed when marrow and CAPS were incubated with malonate and 3-NPA. Mitochondria metabolized CAPS to CAP. FAD, succinate and malonate enhanced CAP formation but reduction of FADH2 was inhibited. While, oxaloacetate, 3-NPA and nitroso-CAP inhibited CAPS metabolism to CAP. Conclusions: These studies demonstrate that CAPS is a competitive substrate for SDH. In marrow and mitochondria, it is oxidized to CAP by SDH and nitro metabolites formed may be responsible for inhibition of SDH. In some marrows presence of SDH isoenzyme may be responsible for both oxidation and nitroreduction of CAPS to CAP, nitroso-CAP and possibly hydroxylamino-CAP. SDH may be a target for CAPS induced marrow toxicity.-
dc.languageengen_HK
dc.publisherHong Kong Medical Association. The Journal's web site is located at http://www.hkmj.org-
dc.relation.ispartofHong Kong Medical Journalen_HK
dc.titleChloramphenicol succinate a competitive substrate and inhibitor of succinate dehydrogenase: relation to its mechanisms of toxicityen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailKumana, CR: hrmekcr@hku.hken_HK
dc.identifier.emailLiang, RHS: rliang@hku.hken_HK
dc.identifier.emailCheung, BMY: mycheung@hku.hken_HK
dc.identifier.authorityLiang, RHS=rp00345en_HK
dc.identifier.hkuros86638en_HK
dc.identifier.volume9en_HK
dc.identifier.spage64en_HK

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