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Mutagenicity, tumor-initiating activity, and metabolism of methylphenanthrenes
Abstract:
The mutagenicity, in vitro metabolism, and tumor-initiating activity of methylphenanthrenes were evaluated. The only monomethyl isomers which were mutagenic toward Salmonella typhimurium were 1- and 9-methylphenanthrenes. Among the disubstituted phenanthrenes assayed for mutagenicity, only 1,4-dimethylphenanthrene was active in the presence of metabolic activation. Studies on the in vitro metabolism of methylphenanthrenes were performed by incubation of the various isomers with the 9000 X g supernatant from Aroclor-treated rat livers. Comparison of mutagenicity with metabolites formed in vitro indicated that inhibition of 9,10-dihydrodiol formation was positively associated with mutagenic activity. Among the metabolites of 1- and 9-methylphenanthrenes, significant mutagenic activity was associated only with the 3,4- and/or 5,6-dihydrodiol. Metabolism to the 1,2- or 7,8-dihydrodiol, the requisite dihydrodiols for formation of "bay-region" dihydrodiol-epoxides, was most significant in the case of 4-methylphenanthrene. None of the isomeric methylphenanthrenes were active when assayed as tumor initiators on mouse skin. In contrast, 1,4-dimethylphenanthrene was found to have potent tumorigenic activity. These results suggest that inhibition of 9,10-dihydrodiol formation, the influence of a 4-methyl substituent in directing dihydrodiol formation at the 1,2- or 7,8-positions, and the presence of a bay-region methyl group may be responsible for eliciting a tumorigenic response for 1,4-dimethylphenanthrene.
Insights
Certain methylphenanthrenes are mutagenic and tumor-initiating. 1,4-dimethylphenanthrene shows potent tumorigenic activity, linked to specific metabolic pathways and dihydrodiol formation inhibition.
Area of Science:
- Polycyclic Aromatic Hydrocarbons (PAHs) Research
- Toxicology and Carcinogenesis
- Metabolic Activation Studies
Background:
- Methylphenanthrenes are a class of polycyclic aromatic hydrocarbons.
- Understanding their mutagenicity and carcinogenicity is crucial for risk assessment.
- Metabolic activation pathways significantly influence the toxicological profile of PAHs.
Purpose of the Study:
- To evaluate the mutagenicity, in vitro metabolism, and tumor-initiating activity of various methylphenanthrene isomers.
- To identify specific structural features and metabolic pathways associated with methylphenanthrene mutagenicity and carcinogenicity.
- To investigate the role of dihydrodiol formation in the carcinogenic mechanism of methylphenanthrenes.
Main Methods:
- Bacterial mutagenicity assays using Salmonella typhimurium with metabolic activation.
- In vitro metabolism studies using rat liver S9 fractions to identify metabolites.
- Tumor initiation assays on mouse skin to assess carcinogenic potential.
Main Results:
- 1- and 9-methylphenanthrenes were mutagenic; 1,4-dimethylphenanthrene was mutagenic with metabolic activation.
- Inhibition of 9,10-dihydrodiol formation correlated positively with mutagenic activity.
- 1,4-dimethylphenanthrene exhibited potent tumor-initiating activity, unlike other isomers tested.
Conclusions:
- Metabolism to specific dihydrodiols, particularly the 3,4- and/or 5,6-dihydrodiols, is linked to the mutagenicity of 1- and 9-methylphenanthrenes.
- Metabolism to 1,2- or 7,8-dihydrodiols, essential for "bay-region" dihydrodiol-epoxide formation, was significant for 4-methylphenanthrene.
- The tumorigenic activity of 1,4-dimethylphenanthrene is likely due to inhibition of 9,10-dihydrodiol formation and the influence of methyl substituents on dihydrodiol epoxide formation.