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Metabolism and distribution of phenanthridine trypanocides in trypanosome Brucei brucei

Boibessot, I. and Grant, M.H. and Turner, M.C.J. and Skellern, G.G. and Watson, D.G. and Goldie, E.I. and Connel, G. and Macintosh, A. (2002) Metabolism and distribution of phenanthridine trypanocides in trypanosome Brucei brucei. Acta Tropica, 84 (3). pp. 219-228. ISSN 0001-706X

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Abstract

Phenanthridine trypanocides (isometamidium chloride hydrochloride, ISM, and Ethidium bromide, EBr) have been widely used to treat African trypanosomiasis in livestock for more than 40 years. Their main action is to inhibit nucleic acid synthesis in trypanosome parasites, by intercalation between the DNA base pairs. They can also linearise selectively kinetoplast DNA minicircles; a form of mitochondrial DNA unique to this group of parasites. However, the metabolism of these compounds by trypanosomes has not been reported. Indeed, it is not known whether or not their metabolism by the parasite contributes to their activity, selective toxicity for these parasites or to the development of chemoresistance. Therefore, we studied the metabolism of EBr and ISM, and their distribution in Trypanosoma brucei (TREU 927) using high performance liquid chromatography (HPLC), liquid chromatography combined with mass spectrometry (LC-MS) and confocal laser scanning microscopy (CLSM). Incubation of EBr with trypanosomes led to the formation of a small amount (0.606±0.191%) of one metabolite (MI). Ion chromatograms extracted from an LC-MS analysis using electrospray ionisation (ESI), showed that the difference in mass between the parent compound and its metabolite was 30. This may correspond to the addition of a hydroxyl and a methyl group. No metabolites could be detected for ISM. The distribution of the two drugs in trypanosomes was investigated by CLSM, using their intrinsic fluorescence. ISM and EBr showed differences in their distribution in trypanosomes. ISM had a greater affinity for the kinetoplast than EBr and it stained other organelles like the flagellum; in contrast the distribution of EBr was more diffuse.

Item type: Article
ID code: 6767
Keywords: phenanthridine trypanocides, trypanosomiasis, kinetoplast, trypanosoma brucei, metabolism, bioengineering, Bioengineering, Human anatomy, Infectious Diseases, Parasitology
Subjects: Technology > Engineering (General). Civil engineering (General) > Bioengineering
Science > Human anatomy
Department: Faculty of Engineering > Bioengineering
Unknown Department
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 28 Aug 2008
    Last modified: 04 Sep 2014 14:51
    URI: http://strathprints.strath.ac.uk/id/eprint/6767

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