| Inhibition of mitochondrial membrane bound-glutathione transferase by mitochondrial permeability transition inhibitors including cyclosporin A. | |
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MedLine Citation:
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PMID: 20226794 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIMS: Effect of mitochondrial permeability transition (MPT) inhibitors on mitochondrial membrane-bound glutathione transferase (mtMGST1) activity in rat liver was investigated in vitro. MAIN METHODS: When mitochondria were incubated with MPT inhibitors, mtMGST1 activity was decreased dose dependently and their 50% inhibition concentration (IC(50)) were 1.2 microM (cyclosporin A; CsA), 31 microM (bongkrekic acid; BKA), 1.8 mM (ADP), and 3.2 mM (ATP). The decrease of mtMGST1 activity by the MPT inhibitors was not observed in the presence of detergent Triton X-100. On the contrary, mtMGST1 inhibition by GST inhibitors such as cibacron blue (IC(50), 4.2 microM) and S-hexylglutathione (IC(50), 480 microM) was not affected in the presence of detergent. Although mtMGST1 resides in both the inner (IMM) and outer mitochondrial membranes (OMM), only mtMGST1 in the IMM was inhibited by the MPT inhibitors in the absence of detergent. GST inhibitors decreased mtMGST1 activity both in the IMM and OMM regardless of the presence or absence of detergent. Cytosolic GSTs and microsomal MGST1 were not inhibited by the MPT inhibitors. KEY FINDINGS: These results indicate that mtMGST1 is inhibited by MPT inhibitors through membrane components, not directly by the inhibitors. SIGNIFICANCE: Since CsA binds to cyclophilin D (Cyp-D) in the mitochondrial matrix whereas BKA or ADP binds to adenine nucleotide translocator (ANT) in the IMM, it was suggested that mtMGST1 in the IMM interacts with Cyp-D/ANT and the binding of MPT inhibitors to Cyp-D or ANT causes their conformational change followed by an alteration of mtMGST1 conformation, resulting in decreasing mtMGST1 activity. |
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Authors:
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Enkhbaatar Ulziikhishig; Kang Kwang Lee; Quazi Sohel Hossain; Yumiko Higa; Naoki Imaizumi; Yoko Aniya |
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Publication Detail:
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Type: Journal Article Date: 2010-03-11 |
Journal Detail:
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Title: Life sciences Volume: 86 ISSN: 1879-0631 ISO Abbreviation: Life Sci. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-05-06 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375521 Medline TA: Life Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 726-32 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Laboratory of Molecular Genetics and Pharmacology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate
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administration & dosage,
pharmacology Animals Bongkrekic Acid / administration & dosage, pharmacology Cyclophilins / metabolism* Cyclosporine / administration & dosage, pharmacology* Cytosol / drug effects, metabolism Dose-Response Relationship, Drug Enzyme Inhibitors / administration & dosage, pharmacology Glutathione Transferase / drug effects*, metabolism Inhibitory Concentration 50 Liver / drug effects, metabolism Male Mitochondrial ADP, ATP Translocases / metabolism Mitochondrial Membrane Transport Proteins / antagonists & inhibitors* Mitochondrial Membranes / metabolism* Protein Binding Protein Conformation / drug effects Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; 11076-19-0/Bongkrekic Acid; 58-64-0/Adenosine Diphosphate; 59865-13-3/Cyclosporine; 9068-80-8/Mitochondrial ADP, ATP Translocases; EC 2.5.1.-/microsomal glutathione S-transferase-I; EC 2.5.1.18/Glutathione Transferase; EC 5.2.1.-/Cyclophilins; EC 5.2.1.8/cyclophilin D |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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