Influence of in vitro ubiquinone antagonists on doxorubicin toxicity in vivo.
Doxorubicin is an anthracycline antibiotic with a very wide spectrum of anticancer activity. It has a great potential for clinical cardiotoxicity, however. One mechanism suggested for the cardiotoxicity is inhibition of ubiquinone-dependent enzymes. It was our purpose to study this possible mechanism using ubiquinone antagonists as probes. The effect on doxorubicin toxicity of three in vitro ubiquinone antagonists was tested in mice. Two of the antagonists, 2-hydroxy-3-n-dodecylmercapto-1,4-naphthoquinone and 2,3-dimethoxy-5-beta-naphthylmercapto-1,4-benzoquinone, enhanced doxorubicin toxicity in vivo as measured by survival. The latter was significantly toxic to mice, by itself. This effect was completely blocked by ubiquinone pretreatment, but only reduced by tocopherol pretreatment. Neither ubiquinone nor tocopherol was able to decrease the toxic interaction between doxorubicin and either of the ubiquinone antagonists. Cardiac and hepatic glutathione reductase and glutathione peroxidase activities were measured in studies using the 2,3-dimethoxy-5-beta-naphthylmercapto-1,4-benzoquinone. This compound appeared to cause a slight reduction in the activity of hepatic glutathione reductase. It appears that these antagonists are not useful to probe the relationship between doxorubicin cardiotoxicity and ubiquinone enzyme inhibition.
Tábora
O
O
Lewandowski
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E
Combs
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AB
D000818:Animals; D016227:Benzoquinones; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D005979:Glutathione Peroxidase / Q000032:analysis; D005980:Glutathione Reductase / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009285:Naphthoquinones / Q000633:toxicity; D011809:Quinones / Q000633:toxicity; D014451:Ubiquinone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D016227:Benzoquinones; D009285:Naphthoquinones; D011809:Quinones; D014451:Ubiquinone; D014810:Vitamin E; C004532:quinone; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase