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The Role of Calcium in The Toxicity of Phenethylbiguanide.

Gettings, Stephen D. (1985) The Role of Calcium in The Toxicity of Phenethylbiguanide. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

The reversal of β-phenethylbiguanide (phenformin) intoxication in mice by disodium succinate confirmed the hypothesis that substrates which transfer reducing equivalents directly to ubiquinone in the mitochondrial respiratory chain, effectively bypass the locus of respiratory inhibition by biguanide anti-diabetic agents in the mitochondrial oxidation of substrates requiring NAD+ as co-factor. Although phenformin bound to liver mitochondria and sub- mitochondrial particles, the drug had no direct inhibitory action upon NADH-ubiquinone oxidoreductase or succinate-ubiquinone oxido- reductase in sub-mitochondrial particles. In coupled mitochondria, phenformin caused a concentration-dependent inhibition of 2-oxo- glutarate oxidation and succinate oxidation. In the absence of extra- mitochondrial Ca2+ , the oxidation of 2-oxoglutarate was less susceptible to inhibition by phenformin: inhibition of succinate oxidation was unaffected. Selective use of various mitochondrial Ca2+ transport inhibitors indicated that significant Ca2+ re-distribution may occur during the isolation of mitochondria. Exposure of guinea-pig, rat or hamster liver mitochondria to phenformin during the isolation procedure resulted in decreased mitochondrial Ca2+ . Novel isolation conditions were developed to determine mitochondrial Ca2+ content considered to reflect that in vivo. The administration of phenformin to rats, guinea pigs or hamsters resulted in decreased mitochondrial Ca2+ which correlated inversely with raised blood lactate concentrations; 2-oxoglutarate oxidation, but not succinate oxidation, was inhibited in these mitochondrial preparations. A mechanism of action of phenformin-associated lactic-acidosis attributable to impaired ATP production arising from inactivation of Ca2+ -sensitive, NAD+ -dependent mitochondrial dehydrogenases (e. g. 2-oxoglutarate dehydrogenase) due to alteration of mitochondrial calcium content is proposed.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Gettings, Stephen D.
Date : 1985
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1985.
Depositing User : EPrints Services
Date Deposited : 24 Apr 2020 15:27
Last Modified : 24 Apr 2020 15:27
URI: http://epubs.surrey.ac.uk/id/eprint/855215

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