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-ami no-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The reactive N-hydr oxylamine metabolites N-hydroxy-IQ and N-hydroxy-PhIP are toxic to iso lated rat cardiomyocytes. This study examined whether antioxidant agen ts protect against N-hydroxyiamine-induced cardiotoxicity. In isolated rat cardiomyocytes, N-acetylcysteine, alpha-tocopherol and glutathion e were protective against N-hydroxylamine-mediated lactate dehydrogena se release into the medium, suggesting that a free radical mechanism m ay be partly involved in HA-induced cardiotoxicity. Since N-acetylcyst eine was by far the most protective of the agents investigated, the ef fects of N-acetylcysteine on HA-induced ultrastructural damage were fu rther examined both in vitro and in vivo. Isolated cardiomyocytes trea ted with 1.2 mM N-acetylcysteine before and during exposure to N-hydro xy-IQ or N-hydroxy-PhIP showed a smaller percentage of ultrastructural abnormalities, such as myofilament loss, sarcoplasmic reticulum swell ing and abnormal mitochondria. N-Acetylcysteine pretreatment also sign ificantly reduced the percentage of cardiac cells with T-tubule dilati on and myelin figures in adult rats dosed with IQ. The protective effe ct of N-acetylcysteine was not associated with a reduction in HA-DNA a dducts, as assessed by P-32-postlabelling analysis of DNA from isolate d cardiomyocytes treated with N-hydroxylamines. DNA adduct formation p er se, therefore, may not be associated with the observed cardiotoxic effects of the HAs. Further studies are required to confirm the involv ement of a free radical mechanism in HA cardiotoxicity.