Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria.

Abstract

Phenformin causes lactic acidosis in clinical situations due to inhibition of mitochondrial respiratory chain complex I. It is reportedly taken up by hepatocytes and exhibits mitochondrial toxicity in the liver. In this study, uptake of phenformin and [(14)C]tetraethylammonium (TEA) and complex I inhibition by phenformin were examined in isolated liver and heart mitochondria. Uptake of phenformin into isolated rat liver mitochondria was higher than that into heart mitochondria. It was inhibited by several cat ionic compounds, which suggests the involvement of multispecific transport system(s). Similar characteristics were also observed for uptake of TEA; however, uptake of phenformin into mitochondria of organic cation/carnitine transporter 1 (OCTN1) knockout mice was lower than that in wild-type mice, whereas uptake of TEA was comparable between the two strains, suggesting the involvement of distinct transport mechanisms for these two cations in mitochondria. Inhibition by phenformin of oxygen consumption via complex I respiration in isolated rat liver mitochondria was greater than that in heart mitochondria, whereas inhibitory effect of phenformin on complex I respiration was similar in inside-out structured submitochondrial particles prepared from rat livers and hearts. Lactic acidosis provoked by iv infusion of phenformin was weaker in octn1(-/-) mice than that in wild-type mice. These observations suggest that uptake of phenformin into liver mitochondria is at least partly mediated by OCTN1 and functionally relevant to its inhibition potential of complex I respiration. This study was, thus, the first to demonstrate OCTN1-mediated mitochondrial transport and toxicity of biguanide in vivo in rodents.

• Authors: Yoshihisa Shitara, Noritaka Nakamichi, Misaki Norioka, Hiroyo Shima, Yukio Kato, Toshiharu Horie
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 132 Issue 1 Pg. 32-42 (Mar 2013) ISSN: 1096-0929 [Electronic] United States
• PMID: 23221006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Organic Cation Transporter 1
• Phenformin
• Electron Transport Complex I
• Carnitine

Topics

• Animals
• Carnitine (metabolism)
• Electron Transport Complex I (antagonists & inhibitors, physiology)
• HEK293 Cells
• Humans
• In Vitro Techniques
• Mice
• Mitochondria, Heart (drug effects, metabolism)
• Organic Cation Transporter 1 (metabolism, physiology)
• Oxygen Consumption
• Phenformin (pharmacokinetics, pharmacology)
• Rats