DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in colon, bladder, and kidney of congenic mice differing in Ah responsiveness and N-acetyltransferase genotype.
Heterocyclic amines, suspected as cancer initiators, require metabolic activation to exert genotoxicity. The food carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) undergoes activation via N-hydroxylation by cytochrome P450 1A2, followed by O-esterification by N-acetyltransferase. We examined the effects of the Ah locus and acetylator polymorphisms (implicated in human colon and bladder cancer risk) on levels of 32P-postlabeled IQ-DNA adducts in C57BL/6 mice congenic for slow acetylation and/or Ah nonresponsiveness. Some were pretreated with beta-naphthoflavone (beta NF), an inducer of cytochromes P450 1A. Guanine adducts were detected in all organs, the predominant one corresponding to N2-(deoxyguanosine-8-yl)-IQ. In the kidney, beta NF pretreatment reduced total adducts by 50% in Ah-responsive animals (P = 0.021); the Ah or acetylator phenotype did not otherwise affect total adducts. In the colon of Ah-nonresponsive animals, rapid acetylators had 3-fold more adducts than slow acetylators (P = 0.0001, vehicle-pretreated; P = 0.0031, beta NF-pretreated). In Ah-responsive mice of either acetylator phenotype, beta NF pretreatment reduced total adducts in the colon by 70% (P = 0.0003). A significant interaction of phenotypes occurred in the bladder; beta NF-pretreatment caused a 2.5-fold increase in adducts but only in the Ah-responsive, rapid acetylator mice. In sum, these polymorphisms influenced the level of IQ-DNA adducts in the kidney, urinary bladder, and colon in complex ways.
Nerurkar
P V
PV
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Schut
H A
HA
Anderson
L M
LM
Riggs
C W
CW
Snyderwine
E G
EG
Thorgeirsson
S S
SS
Weber
W W
WW
Rice
J M
JM
Levy
G N
GN
D000107:Acetylation; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D005260:Female; D005838:Genotype; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D011804:Quinolines / Q000378:metabolism* / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism*
D002273:Carcinogens; D018736:DNA Adducts; D011804:Quinolines; D018336:Receptors, Aryl Hydrocarbon; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase