In this study, we focused on an analysis of biguanides effects on mitochondrial enzyme activities, mitochondrial membrane potential and membrane permeability transition pore function. We used phenformin, which is more efficient than metformin, and evaluated its effect on rat liver mitochondria and isolated hepatocytes. In contrast to previously published data, we found that phenformin, after a 5 min pre-incubation, dose-dependently inhibits not only mitochondrial complex I but also complex II and IV activity in isolated mitochondria. The enzymes complexes inhibition is paralleled by the decreased respiratory control index and mitochondrial membrane potential. Direct measurements of mitochondrial swelling revealed that phenformin increases the resistance of the permeability transition pore to Ca(2+) ions. Our data might be in agreement with the hypothesis of Schäfer (1976) that binding of biguanides to membrane phospholipids alters membrane properties in a non-specific manner and, subsequently, different enzyme activities are modified via lipid phase. However, our measurements of anisotropy of fluorescence of hydrophobic membrane probe diphenylhexatriene have not shown a measurable effect of membrane fluidity with the 1 mM concentration of phenformin that strongly inhibited complex I activity. Our data therefore suggest that biguanides could be considered as agents with high efficacy but low specifity.
- MeSH
- biguanidy farmakologie MeSH
- fenformin farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- jaterní mitochondrie účinky léků enzymologie MeSH
- krysa rodu rattus MeSH
- metformin farmakologie MeSH
- potkani Wistar MeSH
- respirační komplex I antagonisté a inhibitory fyziologie MeSH
- respirační komplex II antagonisté a inhibitory fyziologie MeSH
- respirační komplex IV antagonisté a inhibitory fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- draslík fyziologie MeSH
- finanční podpora výzkumu jako téma MeSH
- fosfáty fyziologie MeSH
- krysa rodu rattus MeSH
- povrchově aktivní látky MeSH
- respirační komplex IV analýza fyziologie MeSH
- srdeční mitochondrie enzymologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
