Formation and removal of DNA adducts in Fischer-344 rats exposed to 2,4-diaminotoluene.
32P-Postlabeling was used to examine DNA adduct formation and removal in Fischer-344 rats exposed to the animal carcinogen 2,4-diaminotoluene (DAT). Adduct formation and persistence were compared between target (liver and mammary gland) and non-target organs (kidney and lung) to determine if possible differences could explain the observed organ specificity of DAT induced carcinogenesis. The effects of different exposure conditions on DNA adduct formation and removal were also examined by varying the concentration and frequency of compound administration. DAT produced three distinct DNA adducts. Among the organs examined, DNA binding was highest in the liver, with levels approximately 10 times greater than that of the mammary gland and up to 50 times greater than of the two nontarget sites. Despite the large differences in the initial extent of adduct formation, the persistence of adducts among sites was not significantly different. In the liver, there were dose-dependent differences in DNA adduct formation, but adduct removal following different dosages did not vary significantly. The effects of multiple administration on DNA adduct formation and removal were examined by treating rats with 5 mg/kg DAT daily for 10 consecutive days. Adduct yields from multiple treatment were greater than from a single 50 mg/kg exposure. The persistence of adducts following multiple treatment was also greater than after an equivalent single exposure. The results demonstrated organ-specific and dose-dependent differences in initial extent of DNA adduct formation, but no differences in adduct persistence. However, the results did suggest that adduct formation and persistence may change with repeated administration of DAT.
La
D K
DK
Department of Environmental Health Sciences, University of California, Los Angeles 90024.
Froines
J R
JR
D000704:Analysis of Variance; D000818:Animals; D002855:Chromatography, Thin Layer; D018736:DNA Adducts / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D010655:Phenylenediamines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D018736:DNA Adducts; D010655:Phenylenediamines; C010914:2,4-diaminotoluene