Energy metabolism modulation by biguanides in comparison with rotenone in rat liver and heart

Arch Toxicol. 2019 Sep;93(9):2603-2615. doi: 10.1007/s00204-019-02519-1. Epub 2019 Jul 19.


The biguanide metformin, a widely used antidiabetic drug, has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. Rotenone, a well-known strong mitochondrial complex I inhibitor, yet associated with toxic effects, has also shown anti-cancer activity. Thus, we compared metformin and phenformin, another biguanide previously on the market as antidiabetic, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. Therefore, we conducted in vivo rat studies with metformin and phenformin, based on an experimental design previously described for mechanistic investigations of the effects of rotenone, including blood and tissue analysis, histopathology and gene expression profiling. These investigations show that the mechanistic profile of phenformin appears similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displays only transient similarities after one day of treatment. A potential reason may be that metformin, but not rotenone or phenformin, self-limits its entry into mitochondria due to its molecular properties. Thus, our detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, but should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.

Keywords: Biguanides; Gene expression; Heart; Liver; Mitochondrial metabolism; Rotenone.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Dose-Response Relationship, Drug
  • Energy Metabolism / drug effects*
  • Gluconeogenesis / drug effects
  • Heart / drug effects*
  • Lactic Acid / blood
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Metformin / pharmacology*
  • Metformin / toxicity
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidative Phosphorylation
  • Phenformin / pharmacology*
  • Phenformin / toxicity
  • Rats, Wistar
  • Rotenone / pharmacology*
  • Rotenone / toxicity
  • Transcriptome / drug effects


  • Antineoplastic Agents
  • Rotenone
  • Lactic Acid
  • Metformin
  • Phenformin