The effects of genetic variation in N-acetyltransferases on 4-aminobiphenyl genotoxicity in mouse liver.
Inbred, congenic and transgenic strains of mice were characterized for acetylation of p-aminobenzoic (PABA) and the carcinogen 4-aminobiphenyl (4ABP). C57Bl/6 mice have the NAT2*8 allele, A/J mice have NAT2*9 and congenic B6.A mice have NAT2*9 on the C57Bl/6 background. The first transgenic strain with human NAT1, the functional equivalent of murine NAT2, was also tested. The murine NAT2*9 allele correlated with a slow phenotype measured with the murine NAT2 selective substrate PABA. The two strains having this allele also had a lower capacity to acetylate 4ABP. A line with five copies of the human NAT1 transgene was bred for at least five generations with either C57Bl/6 or A/J mice. There was no significant change in PABA NAT activity on the C57Bl/6 background but a 2.5-fold increase was seen in hNAT1:A/J compared with A/J. The effect of variation in NATs on 4ABP genotoxicity was assessed in these strains. Twenty-four hours after exposure to a single oral dose of 120 mg 4ABP/kg, hepatic 4ABP-DNA adducts were detected by immunofluoresence in all strains. Nuclear fluorescence intensities (mean+/-S.D.) were 41.1+/-3.6 for C57Bl/6, 37.9+/-1.11 for A/J and 36.3+/-2.44 for B6.A. There was no correlation between murine NAT2 alleles and 4ABP-DNA adduct levels. Similar results were seen with the transgenic strains. The data indicate that the range of variation present in these strains of mice was insufficient to alter susceptibility to 4ABP genotoxicity. The impact of these relatively modest differences in the acetylation of the activation of 4ABP may be masked by other competing biotransformation reactions since 4ABP is a substrate for both NAT1 and NAT2. Mouse models with variation in both isoforms are needed to adequately assess the role of variation in NATs in susceptibility to 4ABP genotoxicity.
McQueen
Charlene A
CA
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, PO Box 210207, Tucson, AZ 85721, USA. mcqueen@pharmacy.arizona.edu
Chau
Binh
B
Erickson
Robert P
RP
Tjalkens
Ronald B
RB
Philbert
Martin A
MA
D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001191:Arylamine N-Acetyltransferase; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*
D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D000611:Aminobiphenyl Compounds; D002352:Carrier Proteins; D018736:DNA Adducts; D007527:Isoenzymes; D009153:Mutagens; C432411:Slc38a1 protein, mouse; C006757:4-biphenylamine; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D010129:4-Aminobenzoic Acid