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Polymorphism of human acetyltransferases

U A Meyer1

  • 1Biocenter of the University of Basel, Switzerland.

Environmental Health Perspectives
|October 1, 1994
PubMed
Summary

Arylamine N-acetyltransferases (NATs) are crucial for drug metabolism. Genetic variations in NAT2, identified through DNA analysis, predict slow or rapid acetylator phenotypes, impacting drug response.

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Area of Science:

  • Pharmacogenomics
  • Enzyme kinetics
  • Molecular biology

Background:

  • Arylamine N-acetyltransferases (NATs) are key enzymes in metabolizing drugs and carcinogens.
  • Human genetic polymorphism in NAT2 leads to distinct slow and rapid acetylator phenotypes, influencing drug efficacy and toxicity.
  • Recent research indicates NAT enzymes also perform N,O-transacetylation and O-acetylation.

Purpose of the Study:

  • To characterize the genetic basis of the human arylamine N-acetyltransferase 2 (NAT2) polymorphism.
  • To identify specific mutations in NAT2 associated with slow and rapid acetylator phenotypes.
  • To develop a DNA-based test for predicting NAT2 metabolic status.

Main Methods:

  • Protein purification, gene cloning, and functional expression of human NAT1 and NAT2.
  • Analysis of NAT2 at the protein, RNA, and DNA levels from phenotyped individuals.
  • Polymerase chain reaction (PCR) to identify and characterize NAT2 mutant alleles.

Main Results:

  • Two human NAT genes, NAT1 and NAT2, were localized to chromosome 8.
  • NAT1 exhibits ubiquitous tissue distribution and high affinity for monomorphic substrates like PABA.
  • NAT2 is primarily expressed in the liver and metabolizes drugs like sulfamethazine; three mutant alleles (M1, M2, M3) were identified, with M1 and M2 being common.

Conclusions:

  • Specific NAT2 mutations explain the common slow and rapid acetylator phenotypes.
  • A PCR-based DNA test can accurately identify over 95% of individuals with mutant NAT2 alleles.
  • This genetic testing enables prediction of drug metabolism phenotype, crucial for personalized medicine.

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