DNA adduct levels in congenic rapid and slow acetylator mouse strains following chronic administration of 4-aminobiphenyl.
4-Aminobiphenyl (4-ABP) is a human and mouse bladder carcinogen. Epidemiological studies have shown that individuals with a slow acetylator phenotype, especially those exposed to high levels of carcinogenic aromatic amines, show an increased susceptibility to bladder cancer. In order to determine if a slow acetylator phenotype results in increased DNA damage, congenic mouse strains C57BL/6J and B6.A-Nat(s), which differ genetically at the acetyltransferase (EC 2.3.1.5) locus as homozygous rapid (Natr/Natr) and homozygous slow (Nat(s)/Nat(s)) acetylators respectively, were continuously administered 4-ABP.HCl (55-300 p.p.m.) in their drinking water for 28 days. The levels of covalently bound N-(deoxyguanosin-8-yl)-4-ABP-DNA adducts, which are believed to be critical for the initiation of tumors, were quantitated in the liver and bladder by 32P-postlabeling analysis. The levels of the hepatic DNA adduct increased with dose in both sexes, but were independent of the mouse acetylator genotype. At comparable doses, however, the levels of DNA adducts were 2-fold higher in the liver of the female as compared to the male animals. The DNA adducts also increased with dose in bladder of the male mice, but in contrast to the liver, the adduct levels were approximately 2-fold lower in the bladder DNA of the female mice. Also in contrast to the liver, the levels of bladder DNA adducts were significantly higher (P < or = 0.03) in the phenotypic rapid acetylator females compared to the slow acetylators at both 75 and 150 p.p.m. doses; the median levels of adducts were 10-20% higher in the phenotypic slow acetylator male bladders compared to their rapid acetylator counterparts. The results of these studies are consistent with the increased carcinogenicity of 4-ABP to the liver of female mice and the bladder of male mice. They further suggest that factors other than acetylator phenotype limit the extent of DNA adduct formation from 4-ABP in these mice.
Flammang
T J
TJ
Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Couch
L H
LH
Levy
G N
GN
Weber
W W
WW
Wise
C K
CK
D000107:Acetylation; D000611:Aminobiphenyl Compounds / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001345:Autoradiography; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005838:Genotype; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010761:Phosphorus Radioisotopes; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism
D000611:Aminobiphenyl Compounds; D010761:Phosphorus Radioisotopes; C006757:4-biphenylamine; C053420:N-(deoxyguanosin-8-yl)-4-aminobiphenyl; D004247:DNA; D003849:Deoxyguanosine