Formation and removal of DNA adducts in the liver of rats chronically fed the food-borne carcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.
Effects of chronic administration of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) at 0.4, 8 and 400 ppm in the diet on DNA adduct formation and removal in the rat liver were examined by the 32P-postlabeling method. The 0.4 and 8 ppm doses for 40 weeks resulted in time-dependent increases in MeIQx-DNA adduct levels until 16 and 8 weeks, respectively, with constant values being maintained thereafter. In the case of a carcinogenic dose (400 ppm) of MeIQx, the adduct levels reached a maximum at week 12, and then gradually decreased. Alteration of metabolism of MeIQx during liver carcinogensis might be related to this decrease in DNA adduct levels. When MeIQx administration was stopped at week 20, 60-90% of the MeIQx-DNA adducts formed with the three doses (0.4, 8 and 400 ppm) of MeIQx were removed in a biphasic manner after return to a basal diet, with initial rapid removal followed by a slow change. No difference in the pattern of MeIQx-DNA adducts was detected on thin layer chromatography at any dose at any time point. Thus, it is suggested that there may be at least two types of damaged DNA, susceptible and resistant to removal of MeIQx-DNA adducts, after chronic administration of MeIQx.
Hirose
M
M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo.
Wakabayashi
K
K
Ochiai
M
M
Kushida
H
H
Sato
H
H
Sugimura
T
T
Nagao
M
M
D000236:Adenoma / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology; D018736:DNA Adducts / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D011810:Quinoxalines / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D002273:Carcinogens; D018736:DNA Adducts; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D005982:Glutathione Transferase