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Analysis of DNA Adducts in Putative Premalignant Hepatic Nodules and Nontarget Tissues of Rats during 2-Acetylaminofluorene Carcinogenesis¹

Department of Pharmacology, Baylor College of Medicine [R. C. G., K. E.], and Department of Pathology, The University of Texas M. D. Anderson Hospital and Tumor Institute [F. F. B.], Houston, Texas 77030

Exposure of rats to a standard four-cycle feeding regimen of 0.06% 2-acetylaminofluorene (AAF) results in the formation of putatively premalignant hepatic nodules, but the types and magnitude of DNA adducts formed in these nodules has not been previously examined. By using a sensitive ³²P-adduct assay (R. C. Gupta, Cancer Res, 45: 5656–5662, 1985), we analyzed the DNA adduct lesions in individual hepatic nodules at various times during and after exposure to AAF. Kidney, spleen, and testis were included as nontarget tissues. No qualitative difference was observed in the DNA adducts found in hepatic nodules and nontarget tissues; however, quantitative differences occurred. At least one unknown and two known (dG-C8-AF and dG-N²-AAF) DNA adducts were detected, with dG-C8-AF being predominantly (96–98%) formed, in all tissues examined. At the end of the first three weeks of AAF feeding, the concentration of the deacetylated adduct dG-C8-AF in liver (223 fmol/µg DNA) was found to be about 2, 6, and 5 times higher than in kidney, spleen, and testis, respectively. The concentration of the N²-acetylated adduct in liver (4.5 fmol/µg DNA) was 4-fold higher than in kidney and strikingly higher (51- and 42-fold, respectively) than in spleen and testis. At the end of the fourth feeding cycle, total DNA adducts measured in the hepatic nodules ranged from 30–100 fmol/µg DNA, while the "surrounding liver," kidney, spleen, and testis showed 235, 218, 62, and 28 fmol adducts/µg DNA, respectively. Sixty days following the cessation of AFF, the binding in both the persistent nodules and liver had decreased to 7% of their respective levels measured at the end of the fourth cycle, while adducts in kidney, spleen, and testis were 32%, 18% and 19%. After 88 days, the binding levels in the nontarget tissues declined further, but no additional adduct removal occurred in the nodules. Our data indicate that (a) although the metabolic apparatus for activation of AAF is diminished in the hepatic nodules, a significant level of adduct formation occurs in the cells of this putative, premalignant lesion, and (b) unlike in the nontarget tissues, repair processes in the premalignant nodules may not be operative several weeks after the cessation of AAF exposure.

¹ This investigation was supported by USPHS Grants CA 30606 (R. C. G.) and CA20657 (F. F. B.) awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.

Received 9/21/87. Revised 5/11/88. Accepted 6/15/88.

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