Inhibition by cyclosporine A of the prooxidant-induced but not of the sodium-induced calcium release from rat kidney mitochondria.
The use of the immunosuppressive drug cyclosporine A (CSA) is restricted by its nephrotoxicity. Perturbation of Ca2+ homeostasis has been implicated in chemical toxicity. Mitochondria, a key regulator of Ca2+ homeostasis, may be a target of the drug. Here we show that CSA inhibits at low concentrations the prooxidant-induced but not the sodium-induced Ca2+ release from rat kidney mitochondria. CSA does not affect Ca2+ uptake by mitochondria. Inhibition of Ca2+ release is due to inhibition of intramitochondrial enzymatic hydrolysis of NAD+ to ADP-ribose and nicotinamide. These findings suggest a very specific effect of CSA on mitochondrial Ca2+ release by which the drug interferes with cellular Ca2+ homeostasis. This is possibly the basis of CSA nephrotoxicity.
Schlegel
J
J
Laboratory of Biochemistry I, Swiss Federal Institute of Technology, Zürich.
Meier
P
P
Kass
G E
GE
Richter
C
C
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006868:Hydrolysis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide
D016877:Oxidants; D010545:Peroxides; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; D000496:Alloxan; D016572:Cyclosporine; D020122:tert-Butylhydroperoxide; D012964:Sodium; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide