Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Abstract

1 The present study evaluated the time-dependency of acute anthracycline cardiotoxicity by varying the duration of exposure -of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C-13 hydroxy metabolite, doxorubicinol.2 Following addition of doxorubicin (175 gM) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 iLM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 gM), however, failed to produce time-related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration-response experiments with doxorubicinol (0.9-7.21EM) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin-treated than in doxorubicinol-treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2" release from isolated SR vesicles, but 3 gM doxorubicinol promoted a 15 fold greater release rate than 3 lM doxorubicin.8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2" loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time-dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2" homeostasis.

Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

“…9,10 These metabolites form a reservoir in the cardiomyocytes and impair contractility through inhibition of Ca 2ϩ and Na ϩ /K ϩ pump activity. 9,20,21 In the human heart, CBRs are considered major anthracycline-metabolizing enzymes. 7,22 Functional polymorphisms in CBR1 and CBR3 modulate the synthesis of anthracycline alcohol metabolites.…”

“…7,8 Development of cardiomyopathy correlates with myocardial accumulation of anthracycline alcohol metabolites. 9,10 Variability in the formation of these metabolites could influence the risk of cardiomyopathy. 7 Synthesis of cardiotoxic alcohol metabolites is catalyzed by myocardial cytosolic carbonyl reductases (CBRs).…”

Doxorubicin Cardiotoxicity

“…Mushlin et al 14 reported that DOX not only progressively diminished contractility but also increased resting force and prolonged 90% relaxation time. Jensen 6 also reported that both the generation of tension and relaxation are impaired in the hearts of rats chronically exposed to DOX.…”

“…11,12 It has been reported that altered calcium handling could lead to the abnormalities of contraction and relaxation observed in DOX-induced cardiomyopathy. 6,7,10,13,14 Recently, many studies have revealed that diastolic dysfunction may represent an earlier manifestation of various types of heart disease than systolic dysfunction, [15][16][17] and it has also been reported that diastolic dysfunction may be an early sign of DOX-induced cardiotoxicity. 18 Although the mechanism for this is still unclear, recent clinical and animal studies of morphologic changes during the early stages of DOXinduced cardiomyopathy have suggested that the sarcoplasmic reticulum (SR), the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of DOX.…”

Defective One- or Two-electron Reduction of the Anticancer Anthracycline Epirubicin in Human Heart

“…Because human myocardium has the same density of water (10,11), the concentrations of DOX or EPI in the strips formally exceeded those added in plasma by factors ranging from 1.4 to 2.1. These results were consistent with the known ability of cardiac tissue to accumulate anthracyclines; however, the accumulation factors determined in this study were significantly lower than those determined by others when studying isolated heart preparations in common laboratory buffers (factors Ն 3; see Ref.…”