N-acetylation pharmacogenetics: a gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits

Proc Natl Acad Sci U S A. 1989 Dec;86(23):9554-7. doi: 10.1073/pnas.86.23.9554.


The New Zealand White rabbit provides a widely used animal model for the human acetylation polymorphism, which confers marked interindividual variation in the effect and toxicity of numerous drugs, chemicals, and potential carcinogens. The relationship of a recently isolated cDNA clone, designated rnat, to genetically polymorphic arylamine N-acetyltransferase (NAT; acetyl-CoA:arylamine N-acetyltransferase, EC of rabbit liver was established by its expression in monkey kidney COS-1 cells: (i) cytosols from transfected cultures contained high levels of an Ac-CoA-dependent NAT activity, which was kinetically indistinguishable from that observed in cytosols from livers of genetically rapid-acetylator rabbits; (ii) transfected cells also contained an immunoreactive protein, recognized by NAT-specific antibodies, with identical electrophoretic mobility to NAT from rabbit liver. The rnat clone and anti-NAT antibodies were then used to study the relationship between NAT activity, liver enzyme protein, and the level of mRNA in livers from in vivo phenotyped rapid- and slow-acetylator rabbits. Livers from slow acetylators were devoid of both immunodetectable NAT protein and its corresponding mRNA. Analysis of genomic DNA with a panel of restriction enzymes revealed the loss of specific hybridizing bands in the DNA of slow-acetylator rabbits. These data strongly suggest that defective arylamine N-acetylation in the rabbit model is caused by a gene deletion resulting in an absence of specific mRNA and NAT enzyme protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acetyltransferases / genetics*
  • Animals
  • Arylamine N-Acetyltransferase / genetics*
  • Arylamine N-Acetyltransferase / isolation & purification
  • Arylamine N-Acetyltransferase / metabolism
  • Blotting, Southern
  • Blotting, Western
  • Cell Line
  • Chromosome Deletion*
  • DNA / genetics
  • Gene Expression
  • Genes*
  • Liver / enzymology*
  • Phenotype
  • Rabbits
  • Restriction Mapping
  • Transfection


  • DNA
  • Acetyltransferases
  • Arylamine N-Acetyltransferase