Retinoids are not able to enhance mitochondrial synthesis of reactive oxygen species
aDepartment of Theoretical Chemistry, University of Poznan, Poznan, Poland, bDepartment of Bioenergetics, Univeristy of Poznan, Poznan, Poland, cdepartment of Physics, Technical University of Poznan, Poznan, Poland
AIMS: This study was undertaken to test a hypothesis that two potent anticancer retinoids, all-trans retinoic acid (atRA) or N-(4-hydroxyphenyl) retinamide (4-HPR) can interfer with mitochondrial electron transfer enhancing synthesis of reactive oxygen species (ROS); a factor inducing apoptosis. METHODS: Mitochondria isolated from liver were incubated with 10 microM atRA or 5microM 4-HPR, and Y-potential as well as oxygen utilization were measured at the same time. Subsequently, synthesis of reactive oxygen species was monitored by spin trap EPR. RESULTS: An uncoupling effect of the retinoids (more pronounced with atRA) on respiration with succinate as oxidizable substrate was observed (i.e. decrease in both ADP/O and respiratory control ratio). Consistently, no enhanced synthesis of ROS by mitochondria treated with the retinoids was observed by EPR. CONCLUSIONS: Both retinoids can be actively metabolized in the mitochondrial respiratory chain as substrates; an unexpected aspect of retinoid metabolism. The retinoids do interact with electron transfer in normal mitochondria. They deconjugate mitochondrial respiration reducing rather than enhancing, synthesis of ROS.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 997 (Chemoprevention).