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PMID: 1706598 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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 Biochemical journal ·Vol. 274 ( Pt 2) ·1991-03-01 ·Pages 611-4

Griffiths EJ, Halestrap AP

Abstract

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.

MeSH Terms
Adjuvants, Immunologic/pharmacology Amino Acid Isomerases/antagonists & inhibitors Animals Anti-Bacterial Agents/pharmacology Calcium/pharmacology Carrier Proteins/antagonists & inhibitors Cyclosporins/pharmacology,toxicity Mitochondria, Heart/drug effects,physiology Mitochondria, Liver/drug effects,physiology Mitochondrial Swelling/drug effects Models, Biological Peptidylprolyl Isomerase Rats Structure-Activity Relationship Tacrolimus
Chemicals
Adjuvants, Immunologic Anti-Bacterial Agents Carrier Proteins Cyclosporins Amino Acid Isomerases Peptidylprolyl Isomerase Calcium Tacrolimus
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Griffiths E J
Department of Biochemistry, School of Medical Sciences, University of Bristol, U.K.
Halestrap A P
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27 references, click to expand
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/bj2740611
Published
1991-03-01
Pages
611-4
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1150183
Subset
IM
External Links
PubMed source DOI: 10.1042/bj2740611 PMC Full Text View journal details
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