Molecular mechanism of the short-term cardiotoxicity caused by 2',3'- dideoxycytidine (ddC): Modulation of reactive oxygen species levels and ADP- ribosylation reactions

Gabriella Skuta, Gabor M. Fischer, Tamas Janaky, Zoltan Kele, Pal Szabo, Jozsef Tozser, Balazs Sumegi

Research output: Article

43 Citations (Scopus)


The short-term cardiac side effects of 2',3'-dideoxycytidine (ddC, zalcitabine) were studied in rats in order to understand the biochemical events contributing to the development of ddC-induced cardiomyopathy. In developing animals, ddC treatment provoked a surprisingly rapid appearance of cardiac malfunctions characterized by prolonged RR, PR, and QT intervals and J point depression. The energy metabolism in the heart was compromised, characterized by a decreased creatine phosphate/creatine ratio (from 2.05 normal value to 0.75) and a decreased free ATP/ADP ratio (from 332 normal value to 121). The activity of respiratory complexes (NADH: cytochrome c oxidoreductase and cytochrome oxidase) also decreased significantly. Southern blot and polymerase chain reaction analysis did not show deletions or a decrease in the quantity of mitochondrial DNA (mtDNA) deriving from ddC- treated rat hearts, indicating that under our experimental conditions, ddC- induced heart abnormalities were not the direct consequence of mtDNA-related damage. The ddC treatment of rats significantly increased the formation of reactive oxygen species (ROS) in heart and skeletal muscle as determined by the oxidation of non-fluorescent dihydrorhodamine123 to fluorescent rhodamine123 and the oxidation of cellular proteins determined from protein carbonyl content. An activation of the nuclear poly-(ADP-ribose) polymerase (EC and an increase in the mono-ADP-ribosylation of glucose- regulated protein and desmin were observed in the cardiac tissue from ddC- treated animals. A decrease in the quantity of heat shock protein (HSP)70s was also detected, while the level of HSP25 and HSP60 remained unchanged. Surprisingly, ddC treatment induced a skeletal muscle-specific decrease in the quantity of three proteins, one of which was identified by N-terminal sequencing as myoglobin, and another by tandem mass spectrometer sequencing as triosephosphate isomerase (EC These data show that the short term cardiotoxicity of ddC is partially based on ROS-mediated signalling through poly- and mono-ADP-ribosylation reactions and depression of HSP70 levels, whose processes represent a new mtDNA independent mechanism for ddC- induced cell damage.

Original languageEnglish
Pages (from-to)1915-1925
Number of pages11
JournalBiochemical Pharmacology
Issue number12
Publication statusPublished - dec. 15 1999

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Molecular mechanism of the short-term cardiotoxicity caused by 2',3'- dideoxycytidine (ddC): Modulation of reactive oxygen species levels and ADP- ribosylation reactions'. Together they form a unique fingerprint.

  • Cite this