Possible role of intracellular Ca2+ in the toxicity of phenformin.
Selective use of various mitochondrial Ca2+ transport inhibitors indicated that significant Ca2+ redistribution may occur during the isolation of mitochondria. Exposure of guinea-pig liver mitochondria to phenformin (beta-phenethylbiguanide) during the isolation procedure resulted in decreased mitochondrial Ca2+. Novel isolation conditions were developed to determine liver mitochondrial calcium content considered to reflect that in vivo. Administration of phenformin to rats and guinea-pigs resulted in decreased mitochondrial Ca2+. Decreased liver mitochondrial Ca2+ correlated inversely with raised blood lactate concentrations in the guinea-pig; 2-oxoglutarate, but not succinate oxidation, was inhibited in these mitochondrial preparations. A mechanism of action for phenformin-associated lactic-acidosis, attributable to impaired mitochondrial function arising from inactivation of Ca2+-sensitive, NAD+-dependent mitochondrial dehydrogenases (e.g. 2-oxoglutarate dehydrogenase) due to alteration in mitochondrial calcium content, is proposed.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology*; D006168:Guinea Pigs; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007773:Lactates / Q000097:blood; D008297:Male; D008634:Mersalyl / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010629:Phenformin / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012430:Ruthenium Red / Q000494:pharmacology; D013045:Species Specificity; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013386:Succinates / Q000378:metabolism
D001786:Blood Glucose; D007656:Ketoglutaric Acids; D007773:Lactates; D013386:Succinates; D012430:Ruthenium Red; D004533:Egtazic Acid; D008634:Mersalyl; D010629:Phenformin; D007655:Ketoglutarate Dehydrogenase Complex; D013385:Succinate Dehydrogenase; D002118:Calcium