Regulation of dimethylnitrosamine metabolism by androgenic hormones

Hormonal regulation of dimethylnitrosamine (DMN) metabolism by mouse kidney microsomes was investigated using an in vitro mutagenesis system that detects bioactive metabolites of this procarcinogen by measuring reverse mutation in Salmonella typhimurium his- auxotrophs. Induction of microsomal DMN metabolizing enzymes was androgen-specific. Testosterone and medroxyprogesterone acetate were active inducers, d/1 norgestrel was less active, while epitestosterone, estradiol, and progesterone were ineffective. THe response to testosterone and medroxyprogesterone acetate was time-and dose-dependent. Eleven strains of inbred mice were screened for their response to exogenous testosterone. DMN metabolism was stimulated in all mouse strains except for RF/J mice. Other androgenic end points were responsive in the latter strain, however. These observations suggest that induction of renal microsomal DMN metabolising enzymes is androgen-specific and probably mediated via the androgen receptor. The insensitivity of RF/J mice may be due to a mutation affecting a key step in the enzymatic activation of DMN.