Neonatal ontogeny of murine arylamine N-acetyltransferases: implications for arylamine genotoxicity

Toxicol Sci. 2003 Jun;73(2):279-86. doi: 10.1093/toxsci/kfg086. Epub 2003 Apr 15.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminobenzoic Acid / pharmacokinetics
  • 4-Aminobenzoic Acid / pharmacology
  • Acetyltransferases*
  • Aging
  • Amino Acid Transport System A
  • Amino Acid Transport Systems*
  • Aminobiphenyl Compounds / pharmacokinetics
  • Aminobiphenyl Compounds / toxicity*
  • Animals
  • Animals, Newborn
  • Arylamine N-Acetyltransferase
  • Biotransformation
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Cytochrome P-450 CYP1A2 / biosynthesis
  • DNA Adducts / analysis
  • DNA Adducts / drug effects
  • Fluorenes / pharmacokinetics
  • Fluorenes / toxicity
  • Isoenzymes
  • Isoniazid / pharmacokinetics
  • Isoniazid / pharmacology
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Mutagens / pharmacokinetics
  • Mutagens / toxicity*
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • Amino Acid Transport System A
  • Amino Acid Transport Systems
  • Aminobiphenyl Compounds
  • Carrier Proteins
  • DNA Adducts
  • Fluorenes
  • Isoenzymes
  • Mutagens
  • RNA, Messenger
  • Slc38a1 protein, mouse
  • 4-biphenylamine
  • 2-aminofluorene
  • Cytochrome P-450 CYP1A2
  • Acetyltransferases
  • Arylamine N-Acetyltransferase
  • N-acetyltransferase 1
  • 4-Aminobenzoic Acid
  • Isoniazid