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Updated: Aug 16, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin
C M Palmeira1, J Serrano, D W Kuehl
1Department of Biochemistry and Molecular Biology, University of Minnesota, School of Medicine, Duluth 55812, USA.
Abstract:
The purpose of this investigation was to determine whether acute doxorubicin intoxication causes a preferential accumulation of 8-hydroxydeoxyguanosine (8OHdG) adducts to mitochondrial DNA (mtDNA) as opposed to nuclear DNA (nDNA), particularly in cardiac tissue. Adult male rats received a single i.p. bolus of doxorubicin (15 mg/kg) and were killed 1-14 days later. Acute intoxication with doxorubicin caused a 2-fold greater increase in 8OHdG adducts to mtDNA compared to nDNA, the concentration of adducts to both nDNA and mtDNA being 20%-40% greater for heart as opposed to liver. For both tissues, the relative abundance of adducts was highest at the earliest time-point examined (24 h) and decreased to control values by 2 weeks. The temporal dilution of 8OHdG adducts was not the result of cell hyperplasia and was only partially due to amplification of the mitochondrial genome, most probably via an increase in DNA copy number rather than a stimulation of mitochondrial biogenesis.
Insights
Acute doxorubicin intoxication preferentially increases mitochondrial DNA (mtDNA) damage over nuclear DNA (nDNA) in rat hearts. This DNA damage, measured as 8-hydroxydeoxyguanosine (8OHdG) adducts, peaked early and resolved within two weeks.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Doxorubicin is a widely used chemotherapy agent.
- Its cardiotoxicity is a significant clinical concern.
- Mitochondrial dysfunction is implicated in doxorubicin-induced damage.
Purpose of the Study:
- To investigate if doxorubicin causes preferential accumulation of 8-hydroxydeoxyguanosine (8OHdG) adducts in mitochondrial DNA (mtDNA) versus nuclear DNA (nDNA).
- To assess this effect specifically in cardiac tissue following acute intoxication.
Main Methods:
- Adult male rats were administered a single dose of doxorubicin (15 mg/kg).
- Cardiac and liver tissues were analyzed for 8OHdG adducts in mtDNA and nDNA at various time points (1-14 days).
Main Results:
- Doxorubicin intoxication led to a 2-fold greater increase in 8OHdG adducts in mtDNA compared to nDNA.
- Cardiac tissue showed a 20%-40% higher concentration of adducts in both mtDNA and nDNA than liver tissue.
- Adduct levels peaked at 24 hours and returned to baseline by 2 weeks, with dilution not solely due to cell proliferation or mitochondrial biogenesis.
Conclusions:
- Acute doxorubicin exposure preferentially damages mtDNA over nDNA, particularly in the heart.
- The observed temporal decrease in adducts is mainly due to dilution, likely via increased DNA copy number rather than enhanced mitochondrial biogenesis.
