Effect of partial hepatectomy on the formation and elimination of 3‐methyldibenzo(c,g)carbazole and 5,9‐dimethyldibenzo(c,g)carbazole‐DNA adducts in mouse liver

Szafarz, D; Valéro, Danièle; Périn, François; Bornecque, Claude

doi:10.1016/0248-4900(90)90292-b

Cited by 4 publications

(2 citation statements)

References 14 publications

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“…On day 2, we found that adduct levels were~20-fold higher in the liver of mice treated with 90 mg/kg than with 10 mg/kg. The time-course of adduct formation after 90 mg/kg, with a peak at early sampling times, was comparable to that reported by Szafarz et al (5) after treatment with~2 mg/kg 3-methylDBC, a derivative of DBC which is much more hepatotoxic than DMDBC. Thus, highdose DMDBC seemed to act in the same way as 3-methylDBC.…”

Section: Discussionsupporting

confidence: 87%

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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5,9-Dimethyldibenzo[c,g]carbazole (DMDBC) is a synthetic derivative of the environmental pollutant 7H-dibenzo[c,g]carbazole. DMDBC is a potent genotoxic carcinogen specific for mouse liver. Using the MutaMouse lacZ transgenic mouse model and a positive selection assay, we measured lacZ mutant frequency (MF) in the liver 28 days after a single s.c. administration of DMDBC at 3, 10, 30, 90 or 180 mg/kg. MF remained low at 3 and 10 mg/kg, but increased markedly from 30 mg/kg onwards. To investigate the reason for this non-linear response, we examined mechanisms potentially involved in mutation induction in the liver. Genotoxic effects such as DNA adduct formation were detected in 32P-post-labelling studies. Liver sections were examined for microscopic changes and cell proliferation. These parameters, and MF, were studied 2, 4, 7, 14, 21 and 28 days after a single s.c. administration of 10 or 90 mg/kg DMDBC. At 10 mg/kg, a dose found to double the MF on day 28, DNA adducts reached a level of 200-600 adducts per 10(8) nucleotides from day 4 to day 28. No changes in histology or cell proliferation were detected at this low dose. At 90 mg/kg, MF increased gradually from day 7 to day 28 (maximum 44-fold). The DNA adduct level ranged from 400 to 4500 adducts per 10(8) nucleotides on day 2, then stabilized at approximately 400 adducts per 10(8) nucleotides on day 4. An early cytotoxic effect was detected microscopically in centrilobular hepatocytes, and was followed by liver cell proliferation. These data suggest that the marked increase in MF in MutaMouse liver after treatment in vivo with DMDBC at 90 mg/kg may be explained by the induction of replicative DNA synthesis due to a cytotoxic effect, allowing the fixation of persistent DNA adducts into mutations.

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Section: Discussionsupporting

confidence: 87%

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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“…Formation of DNA adducts and subsequent mutations leading to malignant conversion of cells is a central tenet of carcinogenic mechanisms proposed for polycyclic aromatic hydrocarbons (1,4,7). However, adduct formation is not sufcient for tumorigenesis and cell proliferation plays a pivotal role in carcinogenesis, contributing to the formation of heritable mutations from DNA lesions and enabling clonal expansion (6,17,25,26,33). Chemically induced cell proliferation may increase cancer-causing mutations either by xing the mutations caused by the DNA adducts, by simply increasing the probability of a spontaneous mutation, and/or providing a selective growth advantage to spontaneous preneoplastic cells.…”

Section: Introductionmentioning

confidence: 99%

Induction of DNA Synthesis in Mouse Liver Following Increases of DNA Adduct Levels Elicited by Very Low Cumulative Doses of the Genotoxic Hepatocarcinogen 7H-dibenzo[c,g]carbazole

et al. 2001

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The purpose of this work was to investigate the administration of very low but repeated doses of a genotoxic carcinogen and an eventual correlation with cellular DNA synthesis. The compound 7H-dibenzo[c,g]carbazole is a genotoxic carcinogen in the mouse liver and was administered topically at the dose of 13.35 microg per animal every 2 days to give a total of 13 applications. Animals were sacrificed 48 hours after every 2 applications until the 10th treatment, then 48 hours after every treatment. Postulated genotoxic effects such as DNA adduct formation were detected by the 32P-post labeling assay. Liver sections were examined for microscopic changes and DNA synthesis. Results showed an increase of the total DNA adduct level in the liver throughout the study with a slowing down in the level after the sixth application of the compound. This change could correspond to the onset of DNA synthesis and to the moderate hepatocellular apoptosis which was observed. The DNA synthesis, which was considered to be secondary to the cytotoxicity induced by the high level of DNA adducts altering normal cellular activity, could also be the opportunity to fix the DNA adducts into heritable mutations. These results raise the question regarding the risk assessment in humans exposed regularly to very low doses of chemicals in the environment: for non-proliferating tissue, the regular accumulation of DNA adducts could remain silent until a "threshold level" is reached from which stimulation of the DNA synthesis may fix the DNA adducts into heritable mutations, eventually leading to tumors.

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Environmental sources, carcinogenicity, mutagenicity, metabolism and DNA binding of nitrogen and sulfur heterocyclic aromatics

Warshawsky

1992

Journal of Environmental Science and Health, Part C

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Effect of partial hepatectomy on the formation and elimination of 3‐methyldibenzo(c,g)carbazole and 5,9‐dimethyldibenzo(c,g)carbazole‐DNA adducts in mouse liver

Cited by 4 publications

References 14 publications

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Induction of DNA Synthesis in Mouse Liver Following Increases of DNA Adduct Levels Elicited by Very Low Cumulative Doses of the Genotoxic Hepatocarcinogen 7H-dibenzo[c,g]carbazole

Environmental sources, carcinogenicity, mutagenicity, metabolism and DNA binding of nitrogen and sulfur heterocyclic aromatics

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