Cardiotoxicity of heterocyclic amine food mutagens in cultured myocytes and in rats.
Cooked meat contains a number of mutagenic/carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP). We recently observed that monkeys treated with IQ showed myocyte degeneration and mitochondrial changes. Thus, it was of interest to develop models to investigate heterocyclic amine cardiotoxicity. Primary cultures of fetal rat myocytes were exposed to the activated forms of the carcinogens (N-OH-IQ and N-OH-PhIP). LDH leakage increased in proportion to the carcinogen dose but was significantly greater in cells exposed to N-OH-IQ than that in cells exposed to N-OH-PhIP. Electron microscopy revealed that treated cells had swollen and irregular mitochondria and fewer organelles. However, DNA adducts, assessed using the 32P-postlabeling method, were significantly higher in myocytes exposed to N-OH-PhIP than in cells exposed to N-OH-IQ. The toxic effects of heterocyclic amines were also evaluated in rats given IQ or PhIP (100 mg/kg, po 10 doses over 2 weeks). Light microscopic and ultrastructural cardiac abnormalities were present in seven of eight rats exposed to IQ or PhIP. Whereas control animals had a normal cardiac morphology, carcinogen-treated animals had foci of chronic inflammation with myocyte necrosis, myofibrillar dissolution and disarray, and dilation of T-tubules. These results suggest that, in addition to being carcinogenic, food mutagens may play a role in cardiac degeneration.
Davis
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CD
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland.
Farb
A
A
Thorgeirsson
S S
SS
Virmani
R
R
Snyderwine
E G
EG
D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000187:drug effects; D005506:Food Contamination; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004272:DNA, Mitochondrial; D007093:Imidazoles; D009153:Mutagens; 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