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Effects of selenium on 1,2-dimethylhydrazine metabolism and DNA alkylation
Abstract:
Sodium selenite (Se) decreases the incidence of colon tumors induced in rats by 1,2-dimethylhydrazine (DMH). In order to determine the basis for this inhibition, we studied the effects of Se on DMH metabolism, DNA alkylation and the rate of cell turnover of the target tissue. The effects of Se pretreatment (4 p.p.m. in the drinking water, for 2, 4 or 6 weeks) on DMH metabolism were monitored in male Sprague-Dawley rats by measuring expired 14CO2 and azo[14C]methane over a 12 h period after a.c. injection of [14C]DMH (20 mg/kg body weight). Compared to control rats, which received only [14C]DMH, Se pretreatment caused an increase in exhaled azomethane (31--69%) and a corresponding decrease in 14CO2 (4--33%) as the length of treatment increased from 2 to 6 weeks. The extent of DNA alkylation (measured as N-7 and O6-methylguanine formation) after Se pretreatment was reduced 20--27% in liver and was increased 40--43% in colon. Metabolic incorporation of [14C] from [14C]DMH into adenine and guanine (presumably via C1 pathways) was reduced 69--72% in colon DNA of Se-treated rats and [3H]thymidine incorporation was reduced 61--65%. This may have been due to decreased cell turnover. A similar response was not observed in the liver. The data suggest that Se decreases hepatic DMH metabolism, and that this may be compensated by an increase in extrahepatic metabolism and alkylation. Although colon alkylation is increased by Se pretreatment, fewer tumors result. This may be due to a decrease in DNA synthesis in this tissue.
Insights
Sodium selenite (Se) reduces colon tumor incidence by altering 1,2-dimethylhydrazine (DMH) metabolism and DNA synthesis. Se decreases DMH breakdown in the liver but increases it in the colon, while reducing DNA alkylation and cell turnover in colon tissue.
Area of Science:
- Biochemistry
- Toxicology
- Cancer Research
Background:
- Sodium selenite (Se) is known to decrease the incidence of colon tumors induced by 1,2-dimethylhydrazine (DMH) in rats.
- The precise mechanisms underlying Se's chemopreventive effects against DMH-induced colon carcinogenesis require further investigation.
Purpose of the Study:
- To elucidate the effects of Se on DMH metabolism, DNA alkylation, and cell turnover in rat colon.
- To understand the biochemical basis for Se's inhibition of DMH-induced colon tumorigenesis.
Main Methods:
- Rats were pretreated with sodium selenite (4 p.p.m. in drinking water) for 2, 4, or 6 weeks.
- DMH metabolism was assessed by measuring expired 14CO2 and azo[14C]methane after [14C]DMH injection.
- DNA alkylation (N-7 and O6-methylguanine), metabolic incorporation of [14C]DMH into DNA bases, and [3H]thymidine incorporation were quantified in liver and colon tissues.
Main Results:
- Se pretreatment increased azomethane exhalation and decreased 14CO2, indicating reduced hepatic DMH metabolism.
- Colon DNA alkylation was increased by Se, while hepatic DNA alkylation was reduced.
- Se significantly decreased metabolic incorporation of DMH into colon DNA bases and reduced [3H]thymidine incorporation, suggesting decreased cell turnover and DNA synthesis.
Conclusions:
- Sodium selenite alters DMH metabolism, decreasing hepatic processing while potentially increasing extrahepatic metabolism.
- Despite increased colon DNA alkylation, Se pretreatment reduces colon tumor incidence, likely due to decreased cell turnover and DNA synthesis.
- These findings highlight a complex interplay between Se, DMH metabolism, DNA damage, and cell proliferation in colon cancer prevention.