Abstract:
:The in vitro and in vivo effects of fluoxetine (and its active metabolite norfluoxetine) on mitochondrial respiration and F0F1-ATPase were studied, respectively, in mitochondria and submitochondrial particles isolated from rat liver. Fluoxetine in vitro inhibited state 3 mitochondrial respiration for alpha-ketoglutarate and succinate oxidations (50% of effect at 0.25 and 0.35 mM drug concentrations, respectively); stimulated state 4 for succinate; and induced a decrease in the respiratory control ratio (RCR) for both oxidizable substrates. The F0F1-ATPase activity was determined at various pH levels in the absence and presence of Triton X-100. The solubilized form was not affected markedly, but an inhibition, apparently non-competitive, was observed for the membrane-bound enzyme, with 50% of the effect at a 0.06 mM drug concentration in pH 7.4. These results suggest that fluoxetine in vitro acts on F0F1-ATPase through direct interaction with the membrane F0 component (similar to oligomycin), or first with mitochondrial membrane and then affecting F0. 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 mitochondrial respiration in state 4 for alpha-ketoglutarate or succinate oxidations 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), indicating uncoupling of oxidative phosphorylation. Pronounced changes were not observed in the K0.5 values of F0F1-ATPase catalytic sites, but the Vmax decreased during the prolonged treatment. The results show that fluoxetine (as well as norfluoxetine) has multiple effects on the energy metabolism of rat liver mitochondria, being potentially toxic in high doses. The drug effects seem to be a consequence of the drug and/or metabolite solubilization in the inner membrane of the mitochondria.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Souza ME,Polizello AC,Uyemura SA,Castro-Silva O,Curti Cdoi
10.1016/0006-2952(94)90283-6subject
Has Abstractpub_date
1994-08-03 00:00:00pages
535-41issue
3eissn
0006-2952issn
1873-2968pii
0006-2952(94)90283-6journal_volume
48pub_type
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