Neonatal ontogeny of murine arylamine N-acetyltransferases: implications for arylamine genotoxicity.
Age-related changes in the expression of xenobiotic biotransformation enzymes can result in differences in the rates of chemical activation and detoxification, affecting responses to the therapeutic and/or toxic effects of chemicals. Despite recognition that children and adults may exhibit differences in susceptibility to chemicals, information about when in development specific biotransformation enzymes are expressed is incomplete. N-acetyltransferases (NATs) are phase II enzymes that catalyze the acetylation of arylamine and hydrazine carcinogens and therapeutic drugs. The postnatal expression of NAT1 and NAT2 was investigated in C57Bl/6 mice. Hepatic NAT1 and NAT2 messenger RNAs (mRNAs) increased with age from neonatal day (ND) 4 to adult in a nonlinear fashion. The presence of functional proteins was confirmed by measuring NAT activities with the isoform selective substrates p-aminobenzoic acid and isoniazid, as well as the carcinogens 2-aminofluorene and 4-aminobiphenyl (4ABP). Neonatal liver was able to acetylate all of the substrates, with activities increasing with age. Protein expression of CYP1A2, another enzyme involved in the biotransformation of arylamines, showed a similar pattern. The genotoxicity of 4ABP was assessed by determining hepatic 4ABP-DNA adducts. There was an age-dependent increase in 4ABP-DNA adducts during the neonatal period. Thus, developmental increases in expression of NAT1 and NAT2 genes in neonates are associated with less 4ABP genotoxicity. The age-related pattern of expression of biotransformation enzymes in mice is consistent with human data for NATs and suggests that this may play a role in developmental differences in arylamine toxicity.
McQueen
Charlene A
CA
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA. mcqueen@pharmacy.arizona.edu
Chau
Binh
B
D010129:4-Aminobenzoic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D000123:Acetyltransferases; D000375:Aging; D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D000611:Aminobiphenyl Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001191:Arylamine N-Acetyltransferase; D001711:Biotransformation; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D005449:Fluorenes / Q000493:pharmacokinetics / Q000633:toxicity; D007527:Isoenzymes; D007538:Isoniazid / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D000611:Aminobiphenyl Compounds; D002352:Carrier Proteins; D018736:DNA Adducts; D005449:Fluorenes; D007527:Isoenzymes; D009153:Mutagens; D012333:RNA, Messenger; C432411:Slc38a1 protein, mouse; C006757:4-biphenylamine; C012177:2-aminofluorene; D019388:Cytochrome P-450 CYP1A2; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D010129:4-Aminobenzoic Acid; D007538:Isoniazid