Induction of antioxidants by adriamycin in mouse heart.
Cardiac oxidative injury is a major limiting factor for clinical application of Adriamycin (ADR) in cancer chemotherapy. ADR depresses some antioxidant systems, thereby further enhancing the cardiotoxicity. Previous studies have shown that ADR inhibits the overall synthesis of DNA, RNA, and protein. It was presumed that the depressed antioxidant activity resulted from the inhibited gene expression. However, there were no experimental data to demonstrate the relationship between the change in antioxidant activities and that in their gene expression. Therefore, the present study was undertaken to examine the effects of ADR on the activities and mRNA abundances of antioxidants in mouse heart. FVB mice (7 weeks old) were treated with ADR (15 mg/kg) by a single i.p. injection. Four days after the treatment, cardiac antioxidant activities and mRNA abundances were measured. The results showed that ADR increased the levels of mRNAs for Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase, glutathione peroxidase (GSHpx), and gamma-glutamylcysteine synthetase (gamma-GCS). On the other hand, ADR increased the activities of catalase and gamma-GCS, and slightly decreased total glutathione concentrations in the heart. Cu,Zn-superoxide dismutase, Mn-superoxide dismutase, and glutathione peroxidase activities were not changed significantly. In addition, ADR increased both mRNA and protein levels of metallothionein in the heart. The data demonstrate that up-regulation of antioxidant gene expression occurred in response to ADR in the mouse heart, although the antioxidant activities were not all increased.
Department of Medicine, University of Louisville, School of Medicine, KY 40202, USA.
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Kang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005979:Glutathione Peroxidase / Q000235:genetics; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D012333:RNA, Messenger; D004317:Doxorubicin; D008668:Metallothionein; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005721:Glutamate-Cysteine Ligase