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Related Experiment Videos

Polymorphisms of N-acetyltransferase genes.

D M Grant1, M Blum, U A Meyer

  • 1Centre for Drug Safety Research, University of Toronto, Canada.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|September 1, 1992
PubMed
Summary

Human liver enzyme activity, arylamine N-acetyltransferase (NAT), varies due to genetic polymorphism, affecting drug response and toxicity. The NAT2 gene locus is identified as the primary site of this human acetylation polymorphism.

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Area of Science:

  • Pharmacogenetics
  • Biochemistry
  • Molecular Biology

Background:

  • Genetic variations in human liver arylamine N-acetyltransferase (NAT) enzyme activity cause significant differences in drug metabolism and carcinogen disposition.
  • This pharmacogenetic variation leads to differential susceptibility to chemically induced toxicity.
  • Understanding these mechanisms is crucial for personalized medicine and risk assessment.

Purpose of the Study:

  • To elucidate the biochemical and molecular mechanisms underlying the human acetylation polymorphism.
  • To identify and characterize the genes responsible for NAT enzyme activity.
  • To investigate the genetic basis of differential drug and carcinogen metabolism.

Main Methods:

  • Cloning of human NAT1 and NAT2 genes.

Related Experiment Videos

  • Analysis of NAT1 and NAT2 expression in human liver cytosol.
  • Characterization of NAT2 isoforms (NAT2A and NAT2B) and their substrate specificity.
  • Assessment of liver enzyme content in slow vs. rapid acetylator phenotypes.
  • Analysis of NAT2 gene transcript levels in slow acetylators.
  • Identification and detection of mutant NAT2 alleles using RFLP and allele-specific PCR.

    • Main Results:

    • Two human genes, NAT1 and NAT2, encoding functional acetylating enzymes NAT1 and NAT2, were cloned.
    • NAT1 and NAT2 are expressed in human liver cytosol, with NAT2 existing as isoforms NAT2A and NAT2B.
    • The NAT2 gene locus is responsible for the human acetylation polymorphism, as its products selectively acetylate polymorphic substrates and are reduced in slow acetylators.
    • NAT1 exhibits kinetic selectivity for monomorphic substrates, independent of the acetylation polymorphism.
    • Reduced NAT2A/B protein levels in slow acetylators are not associated with altered NAT2 gene transcript levels.
    • Three common mutant NAT2 alleles have been identified.

    Conclusions:

    • The NAT2 gene locus is the primary determinant of the human acetylation polymorphism.
    • Phenotypic slow acetylators exhibit reduced levels of NAT2A/B proteins, despite normal NAT2 transcript levels.
    • Mutations within the NAT2 gene locus underlie the observed acetylation polymorphism, offering potential for genotypic detection and prediction of metabolic status.