Metabolic activation and genotoxicity of heterocyclic arylamines.
Because of the potential for human exposure to mutagenic and carcinogenic heterocyclic arylamines in the diet, the carcinogenicity of three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, is being evaluated in nonhuman primates, especially cynomolgus monkeys. Concomitant with the carcinogenicity studies, the metabolic processing, disposition, and DNA-adduct formation of these compounds are being examined in these monkeys. This report highlights the results from studies in monkeys and from in vitro models examining metabolic activation and genotoxicity of HAAs. The extent of in vivo activation of HAAs in monkeys was assessed by measuring DNA adducts in various tissues. Both 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The implications of metabolic activation and DNA-adduct formation to the carcinogenicity of HAAs are discussed.
Snyderwine
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Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892.
Schut
H A
HA
Adamson
R H
RH
Thorgeirsson
U P
UP
Thorgeirsson
S S
SS
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D000072317:Polychlorinated Dibenzodioxins; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity; D011810:Quinoxalines / Q000493:pharmacokinetics* / Q000633:toxicity; D012475:Salmonella / Q000187:drug effects
D006571:Heterocyclic Compounds; D007093:Imidazoles; D000072317:Polychlorinated Dibenzodioxins; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine