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Tissue-specific DNA adduct formation in mice treated with the environmental carcinogen, 7H-dibenzo[c,g]carbazole
Abstract:
Covalent adduction of DNA by chemical agents is commonly thought to be an essential part of the initiation of chemical carcinogenesis. Until recently, assays of DNA damage by covalent binding of chemicals have been restricted mostly to substances that are available in radiolabeled form, which excludes many environmental compounds with carcinogenic potential. In this paper, the binding of non-radioactive 7H-dibenzo[c,g]carbazole (DBC), a known environmental carcinogen, to DNA in female CD-1 mice after s.c. injection of 44 mumol/kg of the compound has been investigated using a 32P-postlabeling assay. DBC showed strong hepatic specificity with a mean total level of 107 adducts per 10(7) nucleotides at 24 h, while much lower levels of binding were seen in kidney, lung, spleen, skin and brain with 4.3, 2.1, 1.3, 0.4 and 0.04 adducts, respectively, per 10(7) nucleotides. Proportions of individual DBC adducts also varied considerably between tissues. The degree of hepatic preference displayed by DBC is not seen with other polycyclic aromatic carcinogens such as benzo[a]pyrene and 2-acetylaminofluorene. The DNA-binding data, together with other hepatotoxic effects of the compound, may be causally related to the known hepatocarcinogenicity of DBC.
Insights
This study investigated the DNA binding of the environmental carcinogen 7H-dibenzo[c,g]carbazole (DBC) in mice. DBC showed significant binding to liver DNA, suggesting a role in its known liver cancer-causing effects.
Area of Science:
- Environmental Science
- Toxicology
- Molecular Biology
Background:
- Covalent DNA adduction is a key step in chemical carcinogenesis.
- Traditional DNA damage assays are limited to radiolabeled compounds, excluding many environmental carcinogens.
- 7H-dibenzo[c,g]carbazole (DBC) is an environmental carcinogen with unknown DNA binding characteristics in vivo.
Purpose of the Study:
- To investigate the DNA binding of non-radioactive 7H-dibenzo[c,g]carbazole (DBC) in mice.
- To determine the tissue specificity and levels of DBC-DNA adducts.
- To explore the relationship between DBC DNA binding and its hepatocarcinogenicity.
Main Methods:
- A 32P-postlabeling assay was used to quantify DBC-DNA adducts.
- Female CD-1 mice were injected subcutaneously with DBC.
- DNA was isolated from various tissues (liver, kidney, lung, spleen, skin, brain) at 24 hours post-injection.
Main Results:
- DBC exhibited strong hepatic specificity, with 107 adducts per 10(7) nucleotides in the liver.
- Significantly lower adduct levels were found in kidney (4.3), lung (2.1), spleen (1.3), skin (0.4), and brain (0.04).
- The proportion of individual DBC adducts varied across tissues, and this hepatic preference differs from other polycyclic aromatic carcinogens.
Conclusions:
- DBC preferentially binds to DNA in the liver of mice.
- This specific DNA binding pattern may explain the known hepatocarcinogenicity of DBC.
- The 32P-postlabeling assay allows for the study of non-radioactive environmental carcinogens' DNA binding.