Prednisolone and azathioprine worsen the cyclosporine A-induced oxidative phosphorylation decrease of kidney mitochondria.
We investigated the effects of cyclosporine A, prednisolone and azathioprine on respiration rates, Ca2+-induced swelling and Ca2+ fluxes of rat kidney mitochondria. The three drugs significantly decreased the succinate induced-respiration rates according to concentration-dependent processes. Each drug inhibited about 10% of the respiratory control ratio, with EC50 of 3.7 x 10(-7) M, 5.8 x 10(-9) M for cyclosporine A and azathioprine respectively. Prednisolone was the most effective (19.2%) acting by a two-step process with EC50 of 9.2 x 10(-12) M and 1.9 x 10(-8) M. The combination of the three drugs developed a higher significant decrease of respiratory control ratio than that of each drug but lower than the sum of their respective effects. Inhibitions of swelling and Ca2+ fluxes through mitochondrial membrane due to the combination were not different from those induced by cyclosporine A alone. The action mechanisms of cyclosporine A and prednisolone were total and partial Ca2+ dependent respectively. Azathioprine appears to act by a Ca2+-independent one. It is concluded that azathioprine and prednisolone may worsen cyclosporine A-induced renal mitochondrial alteration of oxidative phosphorylation.
Simon
N
N
Département de Pharmacologie, Faculté de Médecine de Paris XII, Créteil, France.
Zini
R
R
Morin
C
C
Bree
F
F
Tillement
J P
JP
D000818:Animals; D001379:Azathioprine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000648:ultrastructure*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013386:Succinates / Q000494:pharmacology; D019802:Succinic Acid
D007166:Immunosuppressive Agents; D013386:Succinates; D016572:Cyclosporine; D011239:Prednisolone; D019802:Succinic Acid; D001379:Azathioprine; D002118:Calcium