INHIBITION OF MITOCHONDRIAL COMPLEX-I MAY ACCOUNT FOR IDDM INDUCED BYINTOXICATION WITH THE RODENTICIDE VACOR

Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N-p-n itrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDIM. We report here that Vacor specifically inhibits the NADH :ubiquinone reductase activity of complex I in mammalian mitochondria, The activity of other respiratory enzymes of mitochondria is unaffect ed by Vacor at concentrations that completely inhibit the redox and en ergetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in in sulinoma cells and pancreatic islets and is also consistent with the d oses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in t he high-energy demanding cells of the pancreatic islets. This newly id entified mechanism of the pathological effects resulting from Vacor in toxication could constitute a paradigm in which to understand environm ental or metabolic causes of IDDM.