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Carcinogenicity and metabolic profiles of 6-substituted benzo[a]pyrene derivatives on mouse skin
Abstract:
The ability was tested of appropriate substituents of benzo[a]pyrene (BP) at C-6 to decrease or suppress the carcinogenic activity for these BP derivatives relative to the parent compound. 8-week-old female Swiss mice in 9 groups of 30 were treated on the back with 0.2 mumol of compound in acetone 4 times weekly for 20 weeks. The following compounds were administered: BP, 6-methylbenzo[a]pyrene (BP-6-CH3), 6-hydroxymethylbenzo[a]pyrene (BP-6-CH2OH), benzo[a]pyrene-6-carboxaldehyde (BP-6-CHO), benzo[a]pyrene-6-carboxylic acid, 6-methoxybenzo[a]pyrene, 6-acetoxybenzo[a]pyrene, 6-bromobenzo[a]pyrene, and 6-iodobenzo[a]pyrene. Two additional groups received BP or BP-6-CH3 twice weekly for 20 weeks at a total dose 25% of that above. In addition, the metabolism of selected 6-substituted BP derivatives was studied, using mouse skin homogenates in vitro and mouse skin in vivo. Only four compounds were carcinogenic; the order of potency was BP greater than BP-6-CH3 greater than BP-6-CH2OH and BP-6-CHO. The difference in carcinogenicity between BP-6-CH2OH and BP-6-CHO could not be assessed by this experiment. In a further tumorigenesis experiment the carcinogenicity of BP-6-CH2OH was compared to that of BP-6 CHO, BP-6-CH3 and 6-hydroxymethylbenzo[a]pyrere sulfate ester (BP-6-CH2OSO3Na) on mouse skin. 9-week-old female Swiss mice in groups of 28 were treated at three dose levels with 0.8, 0.2 and 0.05 mumol of compounds in dioxane--dimethyl sulfoxide (75 : 25) twice weekly for 40 weeks. After 40 experimental weeks BP-6-CH2OSO3Na proved to be a more potent carcinogen than BP-6-CH2OH, which, in turn was more active than BP-6-CHO. The greater carcinogenicity of BP-6-CH3 relative to BP-6-CH2OH and BP-6-CHO is confirmed, suggesting that BP-6-CH2OH is not a proximate carcinogenic metabolite for BP-6-CH3. Since BP-6-CHO is a weaker carcinogen than BP-6-CH2OH and is efficiently reduced metabolically to BP-6-CH2OH, the latter compound may be a common proximal carcinogenic metabolite. The stronger potency of BP-6-CH2OSO3Na, compared to its alcohol, suggests that an ester of BP-6-CH2OH might be the ultimate alkylating compound reacting with cellular nucleophiles.
Insights
Benzo[a]pyrene (BP) derivatives with C-6 substituents were tested for carcinogenicity. While some derivatives showed reduced activity, BP-6-methylbenzo[a]pyrene, BP-6-hydroxymethylbenzo[a]pyrene, and BP-6-carboxaldehyde were carcinogenic, with BP-6-methylbenzo[a]pyrene being the most potent.
Area of Science:
- Chemical carcinogenesis
- Polycyclic aromatic hydrocarbons (PAHs)
Background:
- Benzo[a]pyrene (BP) is a potent environmental carcinogen.
- Understanding structure-activity relationships of BP derivatives is crucial for risk assessment.
Purpose of the Study:
- To evaluate the carcinogenic potential of various C-6 substituted benzo[a]pyrene (BP) derivatives in mice.
- To compare the carcinogenicity of BP derivatives with the parent compound, BP.
Main Methods:
- Swiss mice were topically administered BP and its 6-substituted derivatives (e.g., 6-methyl-, 6-hydroxymethyl-, 6-carboxaldehyde-) over 20-40 weeks.
- Tumorigenesis was assessed, and metabolism of selected derivatives was studied in vitro and in vivo.
Main Results:
- Only four tested compounds, including BP, BP-6-methylbenzo[a]pyrene, BP-6-hydroxymethylbenzo[a]pyrene, and BP-6-carboxaldehyde, exhibited carcinogenicity.
- BP-6-methylbenzo[a]pyrene was more potent than BP-6-hydroxymethylbenzo[a]pyrene and BP-6-carboxaldehyde.
- BP-6-hydroxymethylbenzo[a]pyrene sulfate ester was a more potent carcinogen than its alcohol precursor.
Conclusions:
- C-6 substitution can modulate the carcinogenic activity of benzo[a]pyrene.
- BP-6-hydroxymethylbenzo[a]pyrene may be a proximal carcinogenic metabolite, and its sulfate ester could be the ultimate alkylating agent.