Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin.
The Ki values of cyclosporins A, G and H for the peptidyl-prolyl cis-trans isomerase (PPIase) of liver and heart mitochondria are about 2, 20 and 500 nM respectively. This parallels their profile as inhibitors of non-specific pore opening of mitochondria induced by supraphysiological Ca2+ concentrations. The novel immunosuppressant FK-506 gave little inhibition of either process at 5 microM. These data support our previous hypothesis [Halestrap & Davidson (1990) Biochem. J. 268, 153-160] that pore opening involves an interaction between matrix PPIase and the adenine nucleotide translocase. It is suggested that this model may help to clarify the mechanism of action of cyclosporin as an immunosuppressant and its toxic effects on the liver and kidney following prolonged therapy.
Griffiths
E J
EJ
Department of Biochemistry, School of Medical Sciences, University of Bristol, U.K.
Halestrap
A P
AP
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003524:Cyclosporins / Q000494:pharmacology* / Q000633:toxicity; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000187:drug effects*; D008954:Models, Biological; D019696:Peptidylprolyl Isomerase; D051381:Rats; D013329:Structure-Activity Relationship; D016559:Tacrolimus
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D003524:Cyclosporins; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D002118:Calcium; D016559:Tacrolimus