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Age-related acute adriamycin cardiotoxicity in mice
M Matsumura1, K Nishioka, T Fujii
1Department of Pediatrics (Cardiology), Kyoto University Hospital, Japan.
Abstract:
Myocardial mitochondrial function after acute adriamycin exposure was compared in infant and adult mice. Heart mitochondrial were isolated 48 h after an intraperitoneal injection of adriamycin. Concentrations of adriamycin in serum and heart tissue were not significantly different between infant and adult mice. Oxygen consumption (state 3 respiration), and respiratory control ratio (RCR) were studied polarographically. Enzyme activities in the respiratory chain [succinate-cytochrome c reductase (SCCR), NADH-cytochrome c reductase (NCCR), cytochrome c oxidase (CCO)], and adenine nucleotide translocase (ANT) were assayed. After saline injection (control), no significant differences were detected in state 3 respiration, RCR, and enzyme activity of ANT between infant and adult mice. The respective enzyme activities of SCCR, NCCR, and CCO in adult mice were significantly lower than those in infant mice. After adriamycin injection in adult mice, there were significant decreases in state 3 respiration (using glutamate and malate as substrates from 239 +/- 25 to 160 +/- 50 nanoatom O2/min/mg protein), RCR (using glutamate and malate as substrates from 7.2 +/- 1.0 to 4.4 +/- 1.4), and enzyme activities of SCCR (from 279 +/- 30 to 178 +/- 28 nmol/min/mg protein) and NCCR (from 331 +/- 43 to 237 +/- 30 nmol/min/mg protein), but there were no significant changes in infant mice. No significant changes in enzyme activities of CCO and ANT were found in either infant or adult mice following the administration of adriamycin. In conclusion, adriamycin is less toxic on the myocardial mitochondrial function in infant mice than in adult mice.
Insights
Adriamycin is less toxic to infant mouse heart mitochondria than adult mouse heart mitochondria. This study compared myocardial mitochondrial function after adriamycin exposure in infant and adult mice.
Area of Science:
- Biochemistry
- Cardiovascular Science
- Toxicology
Background:
- Adriamycin (doxorubicin) is a widely used chemotherapy agent.
- Cardiotoxicity is a significant dose-limiting side effect of adriamycin treatment.
- Age-dependent differences in adriamycin toxicity are not fully understood.
Purpose of the Study:
- To compare the effects of acute adriamycin exposure on myocardial mitochondrial function in infant and adult mice.
- To investigate age-related differences in adriamycin-induced mitochondrial dysfunction.
Main Methods:
- Mice (infant and adult) received intraperitoneal injections of adriamycin or saline.
- Heart mitochondria were isolated 48 hours post-injection.
- Mitochondrial function was assessed by measuring oxygen consumption (state 3 respiration) and respiratory control ratio (RCR).
- Enzyme activities of the respiratory chain (SCCR, NCCR, CCO) and ANT were determined.
Main Results:
- Serum and heart adriamycin concentrations were similar between infant and adult mice.
- Adult mice showed significant decreases in state 3 respiration, RCR, SCCR, and NCCR activities after adriamycin exposure.
- Infant mice exhibited no significant changes in these parameters following adriamycin administration.
- No significant changes in CCO and ANT enzyme activities were observed in either age group.
Conclusions:
- Adriamycin significantly impairs myocardial mitochondrial function in adult mice.
- Infant mice demonstrate greater resistance to adriamycin-induced myocardial mitochondrial toxicity compared to adult mice.
- Age is a critical factor influencing adriamycin cardiotoxicity at the mitochondrial level.