MOLECULAR MECHANISMS OF DOXORUBICIN-INDUCED CARDIOMYOPATHY - SELECTIVE SUPPRESSION OF REISKE IRON-SULFUR PROTEIN, ADP ATP TRANSLOCASE, AND PHOSPHOFRUCTOKINASE GENES IS ASSOCIATED WITH ATP DEPLETION IN RAT CARDIOMYOCYTES/

Doxorubicin, a cardiotoxic antineoplastic, disrupts the cardiac-specif ic program of gene expression (Kurabayashi, M., Dutta, S. Jeyaseelan, R., and Kedes, L. (1995) Mol. Cell, Biol, 15, 6356-6897), We have now identified neonatal rat cardiomyocyte mRNAs rapidly sensitive to doxor ubicin, or its congener daunomycin, including transcripts of nuclear g enes encoding enzymes critical in production of energy in cardiomyocyt es: ADP/ATP translocase, a heart- and muscle-specific isoform; Reiske iron-sulfur protein (RISP), a ubiquitously expressed electron transpor t chain component; and a muscle isozyme of phosphofructokinase, Loss o f these mRNAs following doxorubicin or daunomycin is evident as early as 2 h and precedes significant reduction of intracellular ATP, ATP le vels in control cardiomyocytes (17.9 +/- 2.9 nM/mg of protein) fall on ly after 14 h and reach residual levels of 10.4 +/- 0.9 nM (doxorubici n; p = <0.006) and 6.7 +/- 1.9 nM (daunomycin; p = <0.001) by 24 h, Lo ss of mRNAs generating ATP was highly selective since mRNAs for other energy production enzymes, (cytochrome c, cytochrome b, and malate deh ydrogenase), and genes important in glycolysis (pyruvate kinase and gl yceraldehyde-3-phosphate dehydrogenase) wore unaffected even at 24 and 48 h, The drugs had no effect on levels of ubiquitously expressed RIS P mRNA in fibroblasts, These findings could link doxorubicin-induced d amage to membranes and signaling pathways with 1) suppression of trans cripts encoding myofibrillar proteins and proteins of energy productio n pathways and 2) depletion of intracellular ATP stores, myofibrillar degeneration, and related cardiotoxic effects.