Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor.
Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. 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 unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses 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 the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.
Esposti
M D
MD
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Ngo
A
A
Myers
M A
MA
D000818:Animals; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000506:poisoning*; D051381:Rats; D012378:Rodenticides / Q000494:pharmacology / Q000506:poisoning*; D013367:Submitochondrial Particles / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D007328:Insulin; D007329:Insulin Antagonists; D010671:Phenylurea Compounds; D012378:Rodenticides; D016660:NAD(P)H Dehydrogenase (Quinone); C012598:pyriminil