ABSTRACT
The cytotoxicity of metronidazole towards CHO cells in culture has been found to be enhanced by the presence of lactate and ethanol. For 20 mM lactate the maximum enhancement was observed with 5 mM metronidazole. The enhancement by lactate was reduced by the additional presence of 5 mM oxamate (an LDH inhibitor) and 5 mM hydroxyethyl oxamate (a metronidazole metabolite). The cytotoxicity of 5 mM metronidazole was also enhanced by the presence of 30 mM ethanol. The results suggest an involvement of dehydrogenase enzyme systems in the hypoxic activation and toxicity of some nitroimidazoles.
Subject(s)
Ethanol/pharmacology , Lactates/pharmacology , Metronidazole/pharmacology , Animals , Cell Survival/drug effects , Cricetinae , Cricetulus , Drug Interactions , Female , L-Lactate Dehydrogenase/antagonists & inhibitors , Lactic Acid , Ovary , Oxamic Acid/analogs & derivatives , Oxamic Acid/pharmacology , Time FactorsABSTRACT
The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in gassed spinner flasks has been investigated. Flagyl (5 mM) was only cytotoxic at high initial cell densities. However, when lactate (20 mM) was included in the medium the cytotoxicity of Flagyl at low cell densities was considerable, and similar to that of misonidazole under the same conditions. The relevance of this "lactate effect" to in vivo systems, and the possible mechanisms involved, are discussed.
Subject(s)
Cell Survival/drug effects , Lactates/pharmacology , Metronidazole/pharmacology , Misonidazole/pharmacology , Nitroimidazoles/pharmacology , Animals , Cells, Cultured , Cricetinae , Cricetulus , Drug Synergism , Female , Ovary/cytologyABSTRACT
The trichloromethyl peroxy radical Cl3COO reacts with tryptophan, tryptophanyl-tyrosine and with lysozyme to form products whose overall absorption spectrum is different from those observed following the reaction of hydroxyl, bromide, thiocyanate or azide radicals. Two spectral components have been identified: a minor component attributed to the neutral tryptophanyl radical which can react with ascorbate and intramolecularly with tyrosine residues and a major component which does not undergo either of these reactions and is probably a radical adduct.
