Document Detail

Effect of anthracycline antibiotics on oxygen radical formation in rat heart.
MedLine Citation:
PMID:  6293697     Owner:  NLM     Status:  MEDLINE    
This investigation examined the effect of the anthracycline antitumor agents on reactive oxygen metabolism in rat heart. Oxygen radical production by doxorubicin, daunorubicin, and various anthracycline analogues was determined in heart homogenate, sarcoplasmic reticulum, mitochondria, and cytosol, the major sites of cardiac damage by the anthracycline drugs. Superoxide production in heart sarcosomes was significantly increased by anthracycline treatment; for doxorubicin, the reaction appeared to follow saturation kinetics with an apparent Km of 112.62 microM, required NADPH as cofactor, was accompanied by the accumulation of hydrogen peroxide, and probably resulted from the transfer of electrons to molecular oxygen by the doxorubicin semiquinone after reduction of the drug by sarcosomal NADPH:cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC Superoxide formation was also significantly enhanced by the anthracycline antibiotics in the mitochondrial fraction. Doxorubicin stimulated mitochondrial superoxide formation in a dose-dependent manner that also appeared to follow saturation kinetics (apparent Km of 454.55 microM); however, drug-related superoxide production by mitochondria required NADH rather than NADPH and was significantly increased in the presence of rotenone, which suggested that the proximal portion of the mitochondrial NADH dehydrogenase complex [NADH:(acceptor) oxidoreductase, EC] was responsible for the reduction of doxorubicin at this site. In heart cytosol, anthracycline-induced superoxide formation and oxygen consumption required NADH and were significantly reduced by allopurinol, a potent inhibitor of xanthine oxidase (xanthine:oxygen oxidoreductase, EC Reactive oxygen production was detected in all of our studies despite the presence of both superoxide dismutase (superoxide:superoxide oxidoreductase, EC and glutathione peroxidase (glutathione:hydrogen peroxide oxidoreductase, EC in each cardiac fraction. These results suggest that free radical formation by the anthracycline antitumor agents, which occurs in the same myocardial compartments that are subject to drug-induced tissue injury, may damage the heart by exceeding the oxygen radical detoxifying capacity of cardiac mitochondria and sarcoplasmic reticulum.
J H Doroshow
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  43     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1983 Feb 
Date Detail:
Created Date:  1983-02-25     Completed Date:  1983-02-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  460-72     Citation Subset:  IM    
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MeSH Terms
Antibiotics, Antineoplastic
Doxorubicin / pharmacology
Glutathione Peroxidase / metabolism
Heart / drug effects
Mitochondria, Heart / metabolism
Myocardium / metabolism*
NADP / metabolism
Naphthacenes / pharmacology
Oxygen / metabolism*
Oxygen Consumption / drug effects
Rats, Inbred Strains
Structure-Activity Relationship
Superoxides / metabolism*
Grant Support
31788-02//PHS HHS
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Naphthacenes; 11062-77-4/Superoxides; 23214-92-8/Doxorubicin; 53-59-8/NADP; 7782-44-7/Oxygen; EC Peroxidase

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