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The metabolism and cellular interactions of some aliphatic nitrogenous carcinogens
Abstract:
The alkylation of nucleic acids of the liver of rats and Syrian hamsters was measured in relation to carcinogenesis by a number of nitrosamines and azoxyalkanes, most of which induce tumors of the liver in both species following chronic treatment. Two compounds, nitroso-2,6-dimethylmorpholine and nitrosobis(2-hydroxypropyl)amine were not liver carcinogens in rats, but did induce liver tumors in hamsters; there was much less alkylation by these compounds in the rat than in the hamster. In both rats and hamsters, azoxymethane produced a greater extent of alkylation, both at N-7 and O-6 guanine, than did nitrosodimethylamine, although the former is no more potent than the latter as a carcinogen in either species. Both methyl groups of azoxymethane gave rise to N-7 methylation. Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) produced considerable methylation of liver nucleic acids in both species, comparable with that by nitrosodimethylamine, and they induce liver tumors in both rats and hamsters. However, in male rats the extent of alkylation by BOP was much smaller than in females and no O-6-methylation was detected in the former; this correlates with the failure of BOP to induce liver tumors in male rats by gavage, whereas liver tumors are induced in females.
Insights
Nitrosamines and azoxyalkanes cause liver cancer by alkylating liver DNA. Alkylation levels in rats and hamsters correlate with tumor formation, with notable sex differences in male rats for BOP-induced tumors.
Area of Science:
- Hepatocarcinogenesis research
- Toxicology and molecular mechanisms of chemical carcinogenesis
Background:
- Nitrosamines and azoxyalkanes are known liver carcinogens in rodents.
- The relationship between DNA alkylation and tumor induction by these compounds requires further elucidation.
- Species and sex-specific differences in carcinogenicity suggest underlying variations in metabolic activation or DNA repair.
Purpose of the Study:
- To investigate the correlation between nucleic acid alkylation in rat and hamster livers and their susceptibility to carcinogenesis by nitrosamines and azoxyalkanes.
- To explore species-specific and sex-specific differences in DNA alkylation patterns in relation to tumor induction.
- To compare the alkylation extent and sites (N-7 and O-6 guanine) induced by various chemical carcinogens.
Main Methods:
- Measurement of nucleic acid alkylation in the livers of rats and Syrian hamsters following chronic exposure to specific nitrosamines and azoxyalkanes.
- Comparative analysis of alkylation levels (N-7 and O-6 guanine) and carcinogenic potency across different compounds and species.
- Correlation of observed alkylation patterns with tumor incidence in the liver.
Main Results:
- Compounds that failed to induce liver tumors in rats showed significantly lower alkylation levels in rat livers compared to hamsters, where they were carcinogenic.
- Azoxymethane induced greater N-7 and O-6 guanine alkylation than nitrosodimethylamine in both species, despite similar carcinogenic potency.
- Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) caused substantial liver nucleic acid alkylation in both sexes and species, correlating with tumor induction.
- Male rats exhibited significantly lower BOP-induced alkylation, particularly O-6-methylation, compared to females, correlating with BOP's failure to induce liver tumors in males.
Conclusions:
- Liver nucleic acid alkylation is a key factor in the hepatocarcinogenesis induced by nitrosamines and azoxyalkanes.
- Species and sex differences in carcinogenicity are strongly associated with variations in the extent and pattern of DNA alkylation.
- The O-6 guanine alkylation appears critical for BOP-induced hepatocarcinogenesis, especially in female rats.