Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide

Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cel ls since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been sugg ested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for inves tigating the ability of nucleophilic agents to interact with and detoxify M G has been developed. This assay utilizes the sensitivity of exponential ph ase cells of an Escherichia coli double mutant lacking the KefB and KefC po tassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death oc curred under these conditions. PTB protected E. coli against MG almost as w ell as aminoguanidine, a compound shown previously to be involved in detoxi fication. The level of protection by PTB against MG was much greater than f or the endogenous nucleophile, glutathione. These data suggested that PTB c ould interact with and detoxify MG. The mechanism of this interaction was c haracterized by NMR and mass spectroscopy.