Androgen receptor-mediated genetic differences in 2-acetylaminofluorene and dimethylnitrosamine mutagenesis in vitro.
When 2-acetylaminofluorene and dimethylnitrosamine mutagenesis rates in the Salmonella/liver in vitro system were studied with C3H/HeJ mouse kidney or liver postmitochondrial supernatant (S-9) fractions, sex differences (male much greater than female) of 10- to 30-fold were found in kidney but not liver. We examined male mice castrated during the neonatal period, the Tfm/Y male, and dihydrotestosterone-treated female mice. The requirement of both testosterone and the androgen receptor is shown to be important in causing the sex difference in 2-acetylaminofluorene and dimethylnitrosamine mutagenesis in the kidney. Swank et al. [J Mol Biol 81:225-243 (1973)] demonstrated that dihydrotestosterone induces beta-glucuronidase activity in the female kidney: 28- to 30-fold in BALB/cJ and SM/J, 12-fold in C3H/HeJ, and 5- to 6-fold in C57BL/6J and RF/J inbred mice. This gene regulation has been characterized and named the Gur locus. 2-Acetylaminofluorene mutagenesis--in kidney but not liver--is markedly enhanced by dihydrotestosterone (P less than 0.01) in the first three, but not the latter three, inbred strains. Covalent binding of 2-acetylaminofluorene metabolites to DNA in the presence of kidney S-9 fractions in vitro is greatly increased in the BALB/cJ but not C57BL/6J female mouse pretreated with dihydrotestosterone. These data suggest that genetic differences at the Gur locus, in combination with the androgen receptor, may play an important role in the sex-specific and tissue-specific conversion of an O-glucuronide of N-hydroxy-2-acetylaminofluorene or N-hydroxy-aminofluorene to active mutagenic intermediates.
D015073:2-Acetylaminofluorene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D004128:Dimethylnitrosamine / Q000633:toxicity*; D005966:Glucuronidase / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D011944:Receptors, Androgen / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D012737:Sex Factors
D011944:Receptors, Androgen; D011987:Receptors, Steroid; D013196:Dihydrotestosterone; D004247:DNA; D015073:2-Acetylaminofluorene; D005966:Glucuronidase; D004128:Dimethylnitrosamine