Protective effect of N-acetylcysteine against heterocyclic amine-induced cardiotoxicity in cultured myocytes and in rats.
Cooked meat contains many mutagenic/carcinogenic heterocyclic amines (HAs), including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The reactive N-hydroxylamine metabolites N-hydroxy-IQ and N-hydroxy-PhIP are toxic to isolated rat cardiomyocytes. This study examined whether antioxidant agents protect against N-hydroxylamine-induced cardiotoxicity. In isolated rat cardiomyocytes, N-acetylcysteine, alpha-tocopherol and glutathione were protective against N-hydroxylamine-mediated lactate dehydrogenase release into the medium, suggesting that a free radical mechanism may be partly involved in HA-induced cardiotoxicity. Since N-acetylcysteine was by far the most protective of the agents investigated, the effects of N-acetylcysteine on HA-induced ultrastructural damage were further examined both in vitro and in vivo. Isolated cardiomyocytes treated with 1.2 mM N-acetylcysteine before and during exposure to N-hydroxy-IQ or N-hydroxy-PhIP showed a smaller percentage of ultrastructural abnormalities, such as myofilament loss, sarcoplasmic reticulum swelling and abnormal mitochondria. N-Acetylcysteine pretreatment also significantly reduced the percentage of cardiac cells with T-tubule dilation and myelin figures in adult rats dosed with IQ. The protective effect of N-acetylcysteine was not associated with a reduction in HA-DNA adducts, as assessed by 32P-postlabelling analysis of DNA from isolated cardiomyocytes treated with N-hydroxylamines. DNA adduct formation per se, therefore, may not be associated with the observed cardiotoxic effects of the HAs. Further studies are required to confirm the involvement of a free radical mechanism in HA cardiotoxicity.
Davis
C D
CD
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
Snyderwine
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EG
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D018736:DNA Adducts / Q000032:analysis; D006321:Heart / Q000187:drug effects*; D006898:Hydroxylamines / Q000633:toxicity; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000648:ultrastructure; D011804:Quinolines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D002273:Carcinogens; D018736:DNA Adducts; D006898:Hydroxylamines; D007093:Imidazoles; D008054:Lipid Peroxides; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase; D000111:Acetylcysteine