2-Aminofluorene-DNA adduct formation in acetylator congenic mouse lines.
The effect of the acetylator polymorphism on hepatic 2-aminofluorene-DNA adduct formation in mice was studied using two recent developments from our laboratory. Acetylator congenic mouse lines differing from their parental inbred lines in N-acetyltransferase activity were used to separate the effect of the N-acetyltransferase polymorphism from effects of differences in other genetically polymorphic enzymes. DNA adduct formation was used as an indicator of arylamine induced DNA damage. Adduct formation was measured by HPLC analysis of 32P-postlabeled nucleotides from hepatic DNA of treated animals. At a high dose (60 mg/kg) of 2-aminofluorene for a 3 h exposure, rapid acetylator mice (C57BL/6J) accumulated twice the adducts of slow acetylators (A/J). In acetylator congenic mice this difference increased so that rapid acetylators with the slow background (A.B6-Natr) had 5- to 7-times the DNA damage of the slow acetylator congenic with the rapid background (B6.A-Nats). It was also found that within each mouse line examined, females had higher levels of adduct formation than males. Acetylator congenic mouse lines were useful in distinguishing the effect of acetylator genes from the total genetic background. Similarly, congenics were useful in demonstrating the contribution that enzymes other than N-acetyltransferase make to differences in adduct formation in inbred mouse lines.
Levy
G N
GN
Department of Pharmacology, University of Michigan, Ann Arbor 48103.
Weber
W W
WW
D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004249:DNA Damage; D005260:Female; D005449:Fluorenes / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011110:Polymorphism, Genetic
C052668:2-aminofluorene-DNA complex; D018736:DNA Adducts; D005449:Fluorenes; D004247:DNA; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase