Regulation of renal N-nitrosodimethylamine demethylase activity by androgens, progestin, glucocorticoid, and estrogen in BALB/c mice.
Studies from this laboratory have shown that renal N-nitrosodimethylamine demethylase (NDMA demethylase), an enzyme responsible for the metabolism of NDMA, shows age- and sex-related differences and is modulated by testosterone. These results have been positively correlated with NDMA-induced mutagenicity and carcinogenicity studies; however, relatively large doses of testosterone (100 mg/kg or 2 mg/day) had been used. The objective of this study was to determine whether this tissue specific increase in renal NDMA demethylase was evident only with pharmacological doses or could be observed at lower doses of testosterone, and, to determine whether this testosterone-induced increase in renal NDMA demethylase was specific for androgenic hormones. BALB/c mice were given injections s.c. of varying doses of testosterone (0.01 to 1.5 mg/day) in 0.1 ml of peanut oil for 1, 4, 8, or 16 days; control mice received peanut oil alone. A 3-fold increase in renal NDMA demethylase was observed within 24 h with 0.01 mg of testosterone. Dose-dependent increases of 3-, 5-, and 11-fold were observed at 0.01, 0.05, and 0.10 mg of testosterone, respectively. Hepatic NDMA demethylase was not affected. To determine whether this induction was specific for androgenic hormones, several hormones (androgens, estrogen, glucocorticoid, and progestin) were used. A 5-, 7-, and 2-fold stimulation of renal NDMA demethylase activity was observed in female mice with 5 alpha-dihydrotestosterone, synthetic androgen methyltrienolone, and androgen agonist medroxyprogesterone acetate, respectively. The biologically inactive 5 beta-dihydrotestosterone, stereomer of 5 alpha-dihydrotestosterone, had no effect. Medroxyprogesterone, methyltrienolone, testosterone, and 5 alpha-dihydrotestosterone exert their effect by interacting with androgen receptors; 5 beta-dihydrotestosterone does not bind to androgen receptors. Dexamethasone or estradiol treatment resulted in a significant inhibition of renal enzyme activity in male mice. None of the treatments affected hepatic NDMA demethylase activities in male or female mice. This rapid and tissue specific stimulation of renal NDMA demethylase with low doses of testosterone or with other androgen agonists seems to be androgen receptor mediated and indicates a physiological relevance of this phenomenon.
Ahir
S
S
Howard University Cancer Center, Washington, DC 20060.
Mohla
S
S
D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003907:Dexamethasone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008525:Medroxyprogesterone / Q000494:pharmacology*; D015741:Metribolone; D051379:Mice; D008807:Mice, Inbred BALB C; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D012016:Reference Values; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology*
D004963:Estrenes; D013196:Dihydrotestosterone; D015741:Metribolone; D013739:Testosterone; D004958:Estradiol; D003907:Dexamethasone; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D008525:Medroxyprogesterone