Polymorphic acetylation of arylamines and DNA-adduct formation.
Inbred mouse strains congenic for rapid and slow N-acetyltransferase (NAT) (A.B6, rapid and B6.A, slow) were used to separate the effect of the NAT polymorphism from the influence of other genetically polymorphic enzymes on DNA adduct formation induced by exposure to arylamine carcinogens. Adduct formation was measured by HPLC analysis of 32P-postlabeled nucleotides from DNA of the urinary bladder and liver. Acetylator phenotype was a significant determinant of DNA damage in females as slow acetylators had higher levels of bladder DNA adducts than rapids. This correlation was the reverse of that seen with liver DNA. Older mice (20-23 weeks) formed much higher bladder DNA adduct levels than young mice (7 week). The increase in bladder adduct formation with age was seen in both sexes of all mouse strains. The older male B6 mice showed a 26-fold increase in bladder adducts and the older females showed no more than a 2-fold increase. In addition, the older male B6 mice produced significant amounts of an unidentified, early eluting adduct peak. Biochemical studies of liver NAT and O-acetyltransferase (OAT) activities showed a direct correlation between the levels of liver 2-aminofluorene (AF) NAT activity and levels of liver DNA-adduct formation, but the role of OAT activity in adduct formation in the mouse remains unclear. These results indicate that the NAT phenotype, age and sex are all important determinants of arylamine-DNA adduct formation in mice.
Weber
W W
WW
Department of Pharmacology, University of Michigan, Ann Arbor 48109-0626.
Levy
G N
GN
Martell
K J
KJ
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005449:Fluorenes / Q000494:pharmacology*; D005838:Genotype; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000494:pharmacology; D012737:Sex Factors; D001743:Urinary Bladder / Q000378:metabolism
D005449:Fluorenes; D009153:Mutagens; C012177:2-aminofluorene; D004247:DNA; D000123:Acetyltransferases