Low glucocorticoid concentrations decrease oxidative phosphorylation of isolated rat brain mitochondria: an additional effect of dexamethasone.
The effects of hydrocortisone, triamcinolone, prednisolone and dexamethasone have been investigated in vitro using mitochondria isolated from rat brain. Respiratory control ratio (RCR), oxygen consumption, ATP synthesis, enzymatic activities of involved complexes and superoxide anion generation have been measured to assess the effects of these drugs. Our data showed that the decrease of RCR induced by glucocorticoids was due to a common inhibition of oxidative phosphorylation (State 3) and of complex V activity and a modification of the proton-fluxes through the mitochondrial inner membrane. These effects were quantitatively limited, since they occurred at concentrations lower than 2 nM. Dexamethasone was the only one able to induce a specific inhibition of complex I activity and to decrease the superoxide anion radical generation. Inhibition of complex V and partial reversion of uncoupling seem to be common properties of glucocorticoids. The theoretical consequence of these inhibitions could be the modulation of the mitochondrial function, oxygen consumption rate, ATP synthase activity and superoxide anion radical production, involved in many patho-physiological phenomena.
Morin
C
C
Département de Pharmacologie, Faculté de Médecine de Paris XII, Créteil, France. tillement@univ-paris12.fr
Zini
R
R
Simon
N
N
Charbonnier
P
P
Tillement
J P
JP
Le Louet
H
H
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006854:Hydrocortisone / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D010766:Phosphorylation; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014221:Triamcinolone / Q000494:pharmacology
D005938:Glucocorticoids; D017382:Reactive Oxygen Species; D014221:Triamcinolone; D003907:Dexamethasone; D011239:Prednisolone; D014450:Electron Transport Complex III; D006854:Hydrocortisone