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DNA adducts and carcinogenicity of nitro-polycyclic aromatic hydrocarbons
P P Fu1, D Herreno-Saenz, L S Von Tungeln
1Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079-9502.
Abstract:
We have been interested in the structure-activity relationships of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), and have focused on the correlation of structural and electronic features with biological activities, including mutagenicity and tumorigenicity. In our studies, we have emphasized 1-, 2-, 3-, and 6-nitrobenzo[a]pyrenes (nitro-B[a]Ps) and related compounds, all of which are derived from the potent carcinogen benzo[a]pyrene. While 1-, 2-, and 3-nitro-B[a]P are potent mutagens in Salmonella, 6-nitro-B[a]P is a weak mutagen. In vitro metabolism of 1- and 3-nitro-B[a]P has been found to generate multiple pathways for mutagenic activation. The formation of the corresponding trans-7,8-dihydrodiols and 7,8,9,10-tetrahydrotetrols suggests that 1- and 3-nitro-B[a]P trans-7,8-diol-9,10-epoxides are ultimate metabolites of the parent nitro-B[a]Ps. We have isolated a DNA adduct from the reaction between 3-nitro-B[a]P trans-7,8-diol-anti9,10-epoxide and calf thymus DNA, and identified it as 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-3-ni tro-B[a]P . The same adduct was identified from in vitro metabolism of [3H]3-nitro-B[a]P by rat liver microsomes in the presence of calf thymus DNA. A DNA adduct of 3-nitro-B[a]P formed from reaction of N-hydroxy-3-amino-B[a]P, prepared in situ with calf thymus DNA was also isolated. This adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubating DNA with 3-nitro-B[a]P in the presence of the mammalian nitroeductase, xanthine oxidase, and hypoxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) like nitro-benzo[a]pyrenes show varying mutagenicity. Researchers identified specific DNA adducts formed by 3-nitro-benzo[a]pyrene metabolites, revealing pathways for mutagenic activation and tumorigenicity.
Area of Science:
- Environmental Chemistry
- Toxicology
- Organic Chemistry
Background:
- Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) are environmental contaminants derived from benzo[a]pyrene.
- Structure-activity relationships of nitro-PAHs are crucial for understanding their biological activities, including mutagenicity and tumorigenicity.
- Nitro-benzo[a]pyrenes (nitro-B[a]Ps), specifically 1-, 2-, 3-, and 6-nitro-B[a]Ps, are key compounds in studying these relationships.
Purpose of the Study:
- To investigate the correlation between structural and electronic features of nitro-PAHs and their biological activities.
- To elucidate the metabolic activation pathways of potent mutagens like 1- and 3-nitro-B[a]P.
- To identify specific DNA adducts formed by nitro-B[a]P metabolites.
Main Methods:
- In vitro metabolism studies using Salmonella assays to determine mutagenicity.
- Isolation and identification of DNA adducts formed from reactions with nitro-B[a]P metabolites and calf thymus DNA.
- Use of rat liver microsomes and mammalian nitroreductases (xanthine oxidase) for metabolic activation studies.
Main Results:
- 1-, 2-, and 3-nitro-B[a]P are potent mutagens, while 6-nitro-B[a]P is a weak mutagen.
- Metabolism of 1- and 3-nitro-B[a]P generates trans-7,8-dihydrodiols and tetrahydrotetrols, suggesting diol-epoxide formation.
- Specific DNA adducts identified: 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-3-nitro-B[a]P and 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P.
Conclusions:
- The formation of specific DNA adducts provides insight into the mutagenic activation mechanisms of nitro-B[a]Ps.
- Metabolic pathways involving diol-epoxides and N-hydroxy metabolites are critical for the genotoxicity of these compounds.
- Understanding these mechanisms is essential for assessing the carcinogenic risk of nitro-PAHs.