Mutagenic activation of IQ, PhIP and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo.
Cooked meat, poultry and fish contain a number of mutagenic and carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In the present study we examined the capacity of hepatic microsomes from Fischer 344 rats, cynomolgus monkeys and humans to metabolically activate IQ, MeIQx and PhIP in vitro using the Ames Salmonella mutagenicity assay. The mutagenic activation of IQ was similar among the three species; however, there were significant differences among the species in the activation of PhIP and MeIQx. Liver microsomes from humans showed the greatest capacity to activate PhIP and MeIQx, followed by rats, and then monkeys. The largest differences between the species were observed when MeIQx was used as the mutagen. MeIQx-DNA adducts formed in vivo were then compared among rats and monkeys given MeIQx by gavage (20 mg/kg/day, 10 doses). 32P-Postlabeling analysis, carried out under intensification conditions, was used to examine MeIQx-DNA adducts in the liver, kidney, heart, colon and white blood cells. MeIQx-DNA adducts were highest in all tissues examined from male rats, followed by female rats, and much lower in monkeys. In the liver, the total MeIQx-DNA adduct levels of monkeys were approximately 19 and approximately 10 times lower than in male and female rats respectively. In extrahepatic tissues, the differences in MeIQx-DNA adduct levels between monkeys and rats were even greater. The results suggest that the low level of MeIQx-DNA adducts found in vivo in cynomolgus monkeys reflects a low capacity to activate MeIQx via the hepatic cytochrome P450 monooxygenase system.
Davis
C D
CD
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Schut
H A
HA
Adamson
R H
RH
Thorgeirsson
U P
UP
Thorgeirsson
S S
SS
Snyderwine
E G
EG
D000818:Animals; D001711:Biotransformation; D004249:DNA Damage; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity; D011810:Quinoxalines / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics; D013045:Species Specificity; D014018:Tissue Distribution
D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine