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Functional characterization of nucleotide polymorphisms in the coding region of N-acetyltransferase 1

A J Fretland1, M A Doll, M A Leff

  • 1Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA.

Pharmacogenetics
|August 16, 2001
PubMed

Insights

Genetic variations in N-acetyltransferase 1 (NAT1) affect carcinogen metabolism and cancer risk. Certain NAT1 alleles lead to reduced enzyme activity and stability, impacting individual susceptibility.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • N-acetyltransferase 1 (NAT1) is crucial for metabolizing carcinogens, and its genetic variations are linked to cancer risk and drug toxicity.
  • Understanding the genotype-phenotype relationship of NAT1 is essential for accurate epidemiological studies.

Purpose of the Study:

  • To investigate the functional impact of NAT1 genetic variants on enzyme activity, protein expression, and stability.
  • To elucidate the role of NAT1 polymorphism in the metabolism of specific carcinogens.

Main Methods:

  • Cloning and expression of human NAT1 reference and allelic variants in yeast (Schizosaccharomyces pombe).
  • Assessing N- and O-acetylation catalytic activities of recombinant NAT1 allozymes.
  • Measuring NAT1 protein expression using Western blot and evaluating mRNA expression and transformation efficiency.
  • Determining the intrinsic stability of NAT1 allozymes.

Main Results:

  • Several NAT1 allelic variants (NAT1*14B, NAT1*15, NAT1*17, NAT1*19, NAT1*22) exhibited significantly reduced catalytic activities.
  • These low-activity alleles showed minimal to undetectable NAT1 protein expression.
  • Recombinant NAT1*17 and NAT1*22 allozymes displayed reduced protein stability compared to the reference NAT1*4.
  • NAT1 allozymes did not catalyze PhIP N-acetylation but showed varied O-acetylation of N-hydroxy-PhIP.

Conclusions:

  • NAT1 genetic polymorphism plays a significant role in the metabolism of aromatic and heterocyclic amine carcinogens.
  • Reduced NAT1 phenotype is associated with allelic variants that lead to decreased NAT1 protein expression and/or reduced protein stability.
  • These findings highlight the importance of NAT1 genotype in determining individual susceptibility to carcinogens and drug toxicities.

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