Formation and differential removal of C-8 and N2-guanine adducts of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline in the liver, kidney, and colorectum of the rat.
Chronic feeding of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the diet results in tumor formation of the liver and colorectum, but does not induce tumorigenesis in the kidney of male Fischer-344 rats. The formation and rate of removal of DNA adducts were investigated in rats given an oral dose of IQ (20 mg/kg) to determine if adduct persistence affects the tissue susceptibility to IQ-induced tumorigenesis. Analysis of DNA adducts by 32P-postlabeling showed the formation of two 2'-deoxyguanosine (dG) adducts, N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-C8-IQ) and 5-(deoxyguanosin-N2-yl)-amino-3-methylimidazo[4,5-f]quinoline (dG-N2-IQ) The pattern and distribution of these dG adducts were similar in all tissues; dG-C8-IQ and dG-N2-IQ accounted for approximately 70% and 15-20%, respectively, of the observed radioactivity. Maximal DNA binding was observed in liver (7.64 +/- 1.08 adducts per 10(7) bases) and in colorectum (1.08 +/- 0.22 adducts per 10(7) bases) 24 h following IQ treatment, while optimal binding appeared in kidney (2.41 +/- 0.47 adducts per 10(7) bases) 72 h after treatment. Greater than 50% of the dG-C8-IQ adduct was removed from DNA of liver and kidney within 1 week of treatment. In contrast, the dG-N2-IQ adduct persisted and was the principal lesion remaining in liver and kidney 4 weeks after treatment with IQ. There was no evidence for selective removal of either adduct in the colorectum over a 3 week period, and adduct removal appeared to be attributed to cell turnover and not due to excision repair processes. Therefore, the relative persistence of dG-C8-IQ and dG-N2-IQ adducts doses not appear to explain tissue susceptibility to IQ-induced neoplasia. The slow disappearance of IQ-DNA adducts suggests that adducts may accumulate during chronic exposure to IQ. Further investigations on DNA adduct formation and removal in animals chronically exposed to this carcinogen may help to explain the susceptibility of various organs to IQ-induced tumorigenesis.
Turesky
R J
RJ
Research Center, Nestec. Ltd., Lausanne, Switzerland.
Markovic
J
J
Aeschlimann
J M
JM
D000821:Animal Feed / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D018736:DNA Adducts / Q000096:biosynthesis* / Q000378:metabolism; D006147:Guanine / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000378:metabolism*
D002273:Carcinogens; D018736:DNA Adducts; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D006147:Guanine