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Mitochondrial sulfhydryl group modification by adriamycin aglycones
1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
FEBS Letters
|July 4, 1988
Summary
Adriamycin aglycones induce calcium (Ca2+) release from heart mitochondria by altering thiol status. This modification of mitochondrial sulfhydryl groups increases inner membrane permeability, a process influenced by drug concentration and anthracycline structure.
Area of Science:
- Biochemistry
- Pharmacology
- Mitochondrial Biology
Background:
- Adriamycin aglycones induce Ca2+ release from rat heart mitochondria at low concentrations.
- This Ca2+ release is linked to increased inner mitochondrial membrane permeability to small molecules.
- Dithiothreitol (DTT) antagonizes this process, suggesting the involvement of thiols.
Purpose of the Study:
- To investigate the role of mitochondrial sulfhydryl groups in adriamycin aglycone-induced Ca2+ release.
- To demonstrate the modification of mitochondrial thiols by adriamycin aglycones.
- To elucidate the mechanism by which adriamycin aglycones alter mitochondrial membrane permeability.
Main Methods:
- Measurement of Ca2+ release from isolated rat heart mitochondria.
- Assessment of mitochondrial sulfhydryl group modification using 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) reactivity.
- Analysis of the dependence of Ca2+ release and sulfhydryl modification on aglycone concentration and C-7 substituent.
Main Results:
- Adriamycin aglycones modify mitochondrial sulfhydryl groups, indicated by decreased DTNB reactivity.
- Both Ca2+ release and sulfhydryl modification show similar dependencies on aglycone concentration and C-7 substituent.
- DTNB itself was found to elicit Ca2+ release from mitochondria.
Conclusions:
- Adriamycin aglycones alter mitochondrial membrane permeability by modifying mitochondrial thiol status.
- The interaction with mitochondrial thiols is a key mechanism for adriamycin aglycone-induced Ca2+ release.
- Targeting mitochondrial thiols may represent a therapeutic strategy related to adriamycin's effects.