Cultured human fibroblasts as a model for evaluation of potential in vivo toxicity of membrane damaging antibiotics |
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Authors: | Monica Thelestam R Möllby |
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Institution: | 1. Department of Bacteriology, Karolinska Institute, S-104 01 Stockholm Sweden;2. Department of Bacteriology, National Bacteriological Laboratory, S-105 21 Stockholm Sweden |
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Abstract: | The toxic side effects of certain antimicrobial agents are probably related to their membrane damaging properties. Thus it should be possible to use measurement of membrane damage in vitro for evaluation of the potential toxicity in vivo of such antibiotics. We estimated the membrane damage induced in cultured human fibroblasts by anti-microbial agents, such as polyene antibiotics, sodium fusidate and polymyxin B as well as derivatives of some of these. Degree and character of membrane damage was determined on basis of leakage of three defined cytoplasmic markers from prelabelled cells after treatment with test substance.By comparing the minimal inhibitory concentrations against the target microbial cells (MIC) with the amounts needed to cause membrane damage of human cells (ED50) a ‘therapeutic dose range’ was obtained (ED50/MIC). The therapeutic dose range and the character of induced membrane damage were compared with the relative toxicities in vivo of each test substance. Highly toxic agents caused large functional ‘holes’ and/or showed a narrow therapeutic dose range, whereas less toxic substances induced smaller functional holes and/or had a larger therapeutic dose range. These parameters, evaluated in the presented model system, should be useful for an indication of potential toxicity in vivo. |
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Keywords: | AIB aminoisobutyric acid AMB amphotericin B AME amphotericin B methyl ester BSS balanced salt solution CTAB cetyltrimethylammonium bromide MEM minimal essential medium MIC minimal inhibitory concentrations TBS tris(hydroxymethyl)aminoethane TES |
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