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PubMed · 12540528

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

Nicolas Simon·Christophe Morin·Saïk Urien·Jean-Paul Tillement·Bernard Bruguerolle
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Abstract

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

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AnimalsKidneyMaleMitochondriaOxidative PhosphorylationRatsRats, WistarSirolimusTacrolimusJournal ArticleResearch Support, Non-U.S. Gov't

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Nicolas Simon, Christophe Morin, Saïk Urien, Jean-Paul Tillement, Bernard Bruguerolle. 2003. Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.. https://doi.org/10.1038/sj.bjp.0705038

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