skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion

Abstract

Synchronized regenerating rat liver after partial hepatectomy was used to study cell cycle-related DNA base alkylation and liver carcinogenesis. A continuous iv infusion of (/sup 14/C)N-nitrosodimethylamine (DMN) at a dose of 0.5 mg/kg/hour was given to inbred male Wistar Af/Han rats over a period of 8 hours either during the G1 phase, hydroxyurea-synchronized DNA synthesis, or the G2+M-phase of regenerating liver or to untreated rats (G0-phase liver--carcinogen dose, 1.5 mg/kg/hour). Two hours after the end of the infusion, the amount of 7-methylguanine was highest in the G0-phase liver, with a decrease in the G1 phase, the S-phase, and the G2+M-phase. After continuous DMN exposure, the O6-methylguanine:7-methylguanine ratio was lower in the S-phase and G2+M-phase livers than in the G0-phase and G1-phase livers, indicating an increased O6-methylguanine repair during DNA synthesis and the G2+M-phase. Liver tumors in rats treated by continuous DMN infusion either during the G0 phase or the S-phase developed only after carcinogen exposure during DNA synthesis.

Authors:
; ;
Publication Date:
Research Org.:
Institute of Pathology, University of Munich, Federal Republic of Germany
OSTI Identifier:
5991610
Alternate Identifier(s):
OSTI ID: 5991610
Resource Type:
Journal Article
Resource Relation:
Journal Name: JNCI, J. Natl. Cancer Inst.; (United States); Journal Volume: 70:1
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 59 BASIC BIOLOGICAL SCIENCES; DNA; ALKYLATION; LIVER; CARCINOGENESIS; NITROSAMINES; BIOLOGICAL EFFECTS; BIOLOGICAL PATHWAYS; CARBON 14 COMPOUNDS; CARCINOMAS; CELL CYCLE; INTRAVENOUS INJECTION; PATHOLOGY; RATS; TRACER TECHNIQUES; AMINES; ANIMALS; BODY; CHEMICAL REACTIONS; DIGESTIVE SYSTEM; DISEASES; GLANDS; INJECTION; INTAKE; ISOTOPE APPLICATIONS; LABELLED COMPOUNDS; MAMMALS; NEOPLASMS; NITROSO COMPOUNDS; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; PATHOGENESIS; RODENTS; VERTEBRATES 560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987); 550201 -- Biochemistry-- Tracer Techniques

Citation Formats

Rabes, H.M., Kerler, R., and Wilhelm, R. DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion. United States: N. p., 1983. Web.
Rabes, H.M., Kerler, R., & Wilhelm, R. DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion. United States.
Rabes, H.M., Kerler, R., and Wilhelm, R. Sat . "DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion". United States. doi:.
@article{osti_5991610,
title = {DNA alkylation and tumor induction in regenerating rat liver after cell cycle-related continuous N-nitrosodimethylamine infusion},
author = {Rabes, H.M. and Kerler, R. and Wilhelm, R.},
abstractNote = {Synchronized regenerating rat liver after partial hepatectomy was used to study cell cycle-related DNA base alkylation and liver carcinogenesis. A continuous iv infusion of (/sup 14/C)N-nitrosodimethylamine (DMN) at a dose of 0.5 mg/kg/hour was given to inbred male Wistar Af/Han rats over a period of 8 hours either during the G1 phase, hydroxyurea-synchronized DNA synthesis, or the G2+M-phase of regenerating liver or to untreated rats (G0-phase liver--carcinogen dose, 1.5 mg/kg/hour). Two hours after the end of the infusion, the amount of 7-methylguanine was highest in the G0-phase liver, with a decrease in the G1 phase, the S-phase, and the G2+M-phase. After continuous DMN exposure, the O6-methylguanine:7-methylguanine ratio was lower in the S-phase and G2+M-phase livers than in the G0-phase and G1-phase livers, indicating an increased O6-methylguanine repair during DNA synthesis and the G2+M-phase. Liver tumors in rats treated by continuous DMN infusion either during the G0 phase or the S-phase developed only after carcinogen exposure during DNA synthesis.},
doi = {},
journal = {JNCI, J. Natl. Cancer Inst.; (United States)},
number = ,
volume = 70:1,
place = {United States},
year = {Sat Jan 01 00:00:00 EST 1983},
month = {Sat Jan 01 00:00:00 EST 1983}
}
  • Analysis, by benzoylated DEAE-cellulose chromatography, has been made of structural change in eu- and heterochromatic DNA from rat liver following administration of the carcinogen N-nitrosodimethylamine. Either hepatic DNA was prelabeled with (/sup 3/H)thymidine administered 2-3 weeks before injection of the carcinogen or the labeled precursor was given during regenerative hyperplasia in rats treated earlier with N-nitrosodimethylamine. Following phenol extraction of either whole liver homogenate or nuclease-fractionated eu- and heterochromatin, carcinogen-modified DNA was examined by stepwise or caffeine gradient elution from benzoylated DEAE-cellulose. In whole DNA, nitrosamine-induced single-stranded character was maximal 4-24 h after treatment, declining rapidly thereafter; gradient elution ofmore » these DNA preparations also provided short-term evidence of structural change. Caffeine gradient chromatography suggested short-term nitrosamine-induced structural change in euchromatic DNA, while increased binding of heterochromatic DNA was evident for up to 3 months after carcinogen treatment. Preparations of newly synthesized heterochromatic DNA from animals subjected to hepatectomy up to 2 months after carcinogen treatment provided evidence of heritable structural damage. Carcinogen-induced binding of heterochromatic DNA to benzoylated DEAE-cellulose was indicative of specific structural lesions whose affinity equalled that of single-stranded DNA up to 1.0 kilobase in length. The data suggest that structural lesions in heterochromatin, which may be a consequence of incomplete repair, are preferentially degraded by endogenous nuclease(s).« less
  • Incorporation of tritiated thymidine into DNA of nuclei isolated from the regenerating livers of rats given 800 r of whole-body radiation 24 hours after partial hepatectctomy has been studied in the presence of a DNA- synthesizizing enzyme system. Immediately after irradiation no diffeference in incorporation was demonstrable between irradiatated and non-irradiated liver nuclei, With increasing time after irradiation, up to 24 hours, incorporation became progressively depressed. At 24 hours after irradiation, incorporation was depressed to the same extent after doses of 200 to 3000 r. Incorporation into nuclei of liver from nonhepatectomized rats was unaffected 24 hours after a dosemore » of 800 r. In contrast to the findings with isolated nuclei, DNA extracted from irradiated regenerating liver, 24 hours after a dose of 800 r, incorporated tritiated thymidine to the same extent as did DNA extracted from non-irradiated regenerating liver. Mechanisms by means to which these findings may be explained are discussed. (auth)« less