Daunorubicin cardiotoxicity: evidence for the importance of the quinone moiety in a free-radical-independent mechanism.
Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98+/-6% at 1 Hz, and 73+/-8 and 67+/-8% for 30 and 60 sec PRP, respectively, and 73+/-3 and 63 +/-3% at 2 and 3 Hz, respectively, for 88 microM Daun (P<0.05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force-frequency relationship or PRP contractions. Additional studies in Ca(2+)-loaded SR microsomes indicated that both Daun and 5-ID opened Ca(2+) release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca(2+) release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.
Shadle
S E
SE
Department of Chemistry, Boise State University, Boise, ID, 83725, USA.
Bammel
B P
BP
Cusack
B J
BJ
Knighton
R A
RA
Olson
S J
SJ
Mushlin
P S
PS
Olson
R D
RD
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000737:chemistry / Q000633:toxicity*; D004285:Dogs; D005260:Female; D005609:Free Radicals / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D006334:Heart Function Tests / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011809:Quinones / Q000737:chemistry / Q000633:toxicity*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D011809:Quinones; D004247:DNA; D002118:Calcium; D003630:Daunorubicin