Use of the 32P-postlabeling method to detect DNA adducts of 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) in monkeys fed IQ: identification of the N-(deoxyguanosin-8-yl)-IQ adduct.
Eight DNA adducts of 2-amino-3-methylimidazolo[4,5-f]-quinoline (IQ) were found by the standard 32P-postlabeling method in livers from male Cynomolgus monkeys fed IQ (5 days/week, 3 weeks, 20 mg/kg, nasal-gastric intubation). The IQ-DNA adduct fingerprints observed in monkeys were identical to those observed in rats that received IQ (0.03%) in the diet for 2 weeks. The C8-guanine-IQ adduct was identified by comigration with the synthetic 3',5'-bisphosphate derivative of N(-deoxyguanosin-8-yl)-IQ. DNA modified in vitro with N-hydroxy-IQ showed seven adducts, including the C8-guanine-IQ adduct, that were identical to those found in monkeys and rats. Thus it appears that N-hydroxy-IQ, the reactive metabolite of IQ, was responsible for all adducts found in vivo, except one. In order to detect adducts in other organs that were present at lower levels, the intensification (ATP-deficient) method for 32P-postlabeling was used. Five of the adducts detected under standard conditions, including the C8-guanine-IQ adduct, were also detected under intensification conditions. The total level of DNA-IQ adducts was highest in the liver, followed by the kidney, colon and stomach, and bladder. The adduct patterns were identical in all organs examined. The results indicate that IQ is potentially genotoxic in primates and therefore a likely human carcinogen.
Snyderwine
E G
EG
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
Yamashita
K
K
Adamson
R H
RH
Sato
S
S
Nagao
M
M
Sugimura
T
T
Thorgeirsson
S S
SS
D000818:Animals; D001345:Autoradiography / Q000379:methods; D004247:DNA / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000302:isolation & purification; D008252:Macaca fascicularis; D008297:Male; D009153:Mutagens / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D011804:Quinolines / Q000302:isolation & purification* / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D009153:Mutagens; D010761:Phosphorus Radioisotopes; D011804:Quinolines; C056105:N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazolo(4,5-f)quinoline; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; D003849:Deoxyguanosine