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Induction of antioxidants by adriamycin in mouse heart
1Department of Medicine, University of Louisville, School of Medicine, KY 40202, USA.
Abstract:
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.
Insights
Adriamycin (ADR) chemotherapy increases antioxidant gene expression in mouse hearts, but not all antioxidant activities are enhanced, potentially explaining cardiotoxicity.
Area of Science:
- Biochemistry
- Cardiology
- Pharmacology
Background:
- Adriamycin (ADR) cardiotoxicity is a significant limitation in cancer chemotherapy.
- ADR impairs antioxidant systems, exacerbating cardiac damage.
- Previous research suggested ADR-induced gene expression inhibition affects antioxidant activity.
Purpose of the Study:
- To investigate the impact of ADR on the expression and activity of cardiac antioxidants.
- To determine the relationship between ADR-induced changes in antioxidant mRNA levels and enzyme activities.
Main Methods:
- FVB mice were administered a single dose of Adriamycin (15 mg/kg).
- Cardiac antioxidant activities and mRNA abundances were assessed four days post-treatment.
- Key antioxidants measured included Cu,Zn-superoxide dismutase, catalase, glutathione peroxidase, and gamma-glutamylcysteine synthetase.
Main Results:
- ADR treatment elevated mRNA levels for multiple antioxidants, including Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase, glutathione peroxidase (GSHpx), and gamma-glutamylcysteine synthetase (gamma-GCS).
- Catalase and gamma-GCS activities increased, while total glutathione levels slightly decreased.
- Metallothionein mRNA and protein levels were also upregulated by ADR.
Conclusions:
- ADR induces an upregulation of antioxidant gene expression in the mouse heart.
- Despite increased gene expression, not all antioxidant enzyme activities are significantly enhanced, suggesting a complex response to ADR-induced oxidative stress.