EFFECT OF FLUOXETINE ON RAT-LIVER MITOCHONDRIA

The in vitro and in vivo effects of fluoxetine (and its active metabol ite norfluoxetine) on mitochondrial respiration and F0F1-ATPase were s tudied, respectively, in mitochondria and submitochondrial particles i solated from rat liver. Fluoxetine in vitro inhibited state 3 mitochon drial respiration for alpha-ketoglutarate and succinate oxidations (50 % of effect at 0.25 and 0.35 mM drug concentrations, respectively); st imulated state 4 for succinate; and induced a decrease in the respirat ory control ratio (RCR) for both oxidizable substrates. The F0F1-ATPas e activity was determined at various pH levels in the absence and pres ence of Triton X-100. The solubilized form was not affected markedly, but an inhibition, apparently non-competitive, was observed for the me mbrane-bound enzyme, with 50% of the effect at a 0.06 mM drug concentr ation in pH 7.4. These results suggest that fluoxetine in vitro acts o n F0F1-ATPase through direct interaction with the membrane F-0 compone nt (similar to oligomycin), or first with mitochondrial membrane and t hen affecting F-0. A very similar behavior concerning the respiratory parameters and F0F1-ATPase properties was observed with norfluoxetine. The in vivo studies with fluoxetine showed stimulation of mitochondri al respiration in state 4 for alpha-ketoglutarate or succinate oxidati ons in acute or prolonged treatments (1 hr after a single i.p. dose of 20 mg of drug/kg of body weight, and 22 hr after 12 days of treatment with a daily dose of 10 mg/kg of body weight, respectively), indicati ng uncoupling of oxidative phosphorylation. Pronounced changes were no t observed in the K-0.5 values of F0F1-ATPase catalytic sites, but the V-max decreased during the prolonged treatment. The results show that fluoxetine (as well as norfluoxetine) has multiple effects on the ene rgy metabolism of rat liver mitochondria, being potentially toxic in h igh doses. The drug effects seem to be a consequence of the drug and/o r metabolite solubilization in the inner membrane of the mitochondria.