An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice

Biochem Biophys Res Commun. 2008 May 30;370(2):285-8. doi: 10.1016/j.bbrc.2008.03.085. Epub 2008 Mar 26.

Abstract

Genetic variation in human N-acetyltransferases (NAT) has been implicated in susceptibility to aromatic amine and hydrazine carcinogens and therapeutic drugs. There are mouse models for variability of human NAT1; however mice with genetic differences in Nat1 (corresponding to human NAT2), have not been available. N-Ethyl-N-nitrosourea (ENU) mutagenesis was used to create genetic variation in Nat1. Among a number of mutations identified, a base-pair change substituting threonine for isoleucine at position 95 was recovered and studied. Molecular models suggested that this substitution would alter substrate binding. Analysis of hepatic Nat1 activity with the selective substrate isoniazid showed that there was a significant reduction in enzymatic activity in the homozygous mutants compared to the parental strain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology*
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Arylamine N-Acetyltransferase / analysis
  • Arylamine N-Acetyltransferase / genetics*
  • Cats
  • Cricetinae
  • Ethylnitrosourea / pharmacology*
  • Genetic Variation
  • Humans
  • Isoenzymes / analysis
  • Isoenzymes / genetics*
  • Liver / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutagenesis*
  • Mutation
  • Rabbits
  • Rats
  • Substrate Specificity / genetics

Substances

  • Alkylating Agents
  • Isoenzymes
  • Arylamine N-Acetyltransferase
  • N-acetyltransferase 1
  • Ethylnitrosourea