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 ¹⁴ CO ₂ and azo[ ¹⁴ C]methane over a 12 h period after a s.c. injection of [ ¹⁴ C]DMH (20 mg/kg body weight). Compared to control rats, which received only [ ¹⁴ C]DMH, Se pretreatment caused an increase in exhaled azomethane (31–69%) and a corresponding decrease in ¹⁴ CO ₂ (4–33%) as the length of treatment increased from 2 to 6 weeks. The extent of DNA alkylation (measured as N-7 and O ⁶ -methylguanine formation) after Se pretreatment was reduced 20–27% in liver and was increased 40–43% in colon. Metabolic incorporation of [ ¹⁴ C] from [ ¹⁴ C]DMH into adenine and guanine (presumably via Q 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 ex-trahepatic 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.