Smolen T N, Brewer J A, Weber W W
Institute for Behavioral Genetics, University of Colorado, Boulder.
J Pharmacol Exp Ther. 1993 Feb;264(2):854-8.
N-acetylation participates in the biotransformation of hydrazine drugs and arylamine carcinogens to cytotoxic and carcinogenic products. Differences in acetylation capacity expressed in several mammalian species, including humans and mice, are associated with differences in toxicity and carcinogenicity from these chemicals. The present study examines the influence of genotype, age and sex on kidney N-acetyltransferase (NAT) activity in C57BL/6J (B6) and A/J inbred mouse strains using p-amino-benzoic acid (PABA) as a substrate. There were no strain differences in kidney PABA NAT activity. However, within these strains, males have greater kidney NAT activity than females. A 2-fold increase in kidney NAT activity of males was evident by 30 days postnatally and persisted into maturity (> 200 days after birth), whereas the kidney NAT activity of females remained unchanged. Castration reduced male kidney NAT to female levels, whereas testosterone replacement restored original levels of activity. Ovariectomized females exhibited the same enzyme activity as intact females. Testosterone increased kidney NAT activity in females, but not in intact males. Estradiol decreased kidney NAT in males, but had no effect on female NAT activity. The data suggest that the increase in kidney NAT activity in male mice that accompanies development is under androgenic control. This idea is further supported by our finding that the kidney NAT activity of androgen-insensitive tfm/y mice is significantly less than the activity of either females or males sharing the same genetic background. These observations may explain, in part, the higher susceptibility of male mice to 2-acetylaminofluorene mutagenicity and carcinogenicity.
