• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jul 15, 1991; 88(14): 6333–6337.
PMCID: PMC52077

Diverse point mutations in the human gene for polymorphic N-acetyltransferase.

Abstract

Classification of humans as rapid or slow acetylators is based on hereditary differences in rates of N-acetylation of therapeutic and carcinogenic agents, but N-acetylation of certain arylamine drugs displays no genetic variations. Two highly homologous human genes for N-acetyltransferase (NAT; arylamine acetyltransferase, acetyl CoA:arylamine N-acetyltransferase, EC 2.3.1.5), NAT1 and NAT2, presumably code for the genetically invariant and variant NAT proteins, respectively. In the present investigation, 1.9-kilobase human genomic EcoRI fragments encoding NAT2 were generated by the polymerase chain reaction with liver and leukocyte DNA from seven subjects phenotyped as homozygous and heterozygous acetylators. Direct sequencing revealed multiple point mutations in the coding region of two distinct NAT2 variants. One of these was derived from leukocytes of a slow acetylator and was distinguished by a silent mutation (codon 94) and a separate G----A transition (position 590) leading to replacement of Arg-197 by Gln; the mutated guanine was part of a CpG dinucleotide and a Taq I site. The second NAT2 variant originated from liver with low N-acetylation activity. It was characterized by three nucleotide transitions giving rise to a silent mutation (codon 161), accompanied by obliteration of the sole Kpn I site, and two amino acid substitutions: Thr for Ile (codon 114) and Arg for Lys (codon 268). Heterozygosity was detected in three NAT2 samples: two were heterozygous for the rapid and one of the allelic variants, and the third was a compound heterozygote of both mutant alleles. The results show conclusively that the genetically variant NAT is encoded by NAT2.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Weber WW, Hein DW. N-acetylation pharmacogenetics. Pharmacol Rev. 1985 Mar;37(1):25–79. [PubMed]
  • Andres HH, Klem AJ, Schopfer LM, Harrison JK, Weber WW. On the active site of liver acetyl-CoA. Arylamine N-acetyltransferase from rapid acetylator rabbits (III/J). J Biol Chem. 1988 Jun 5;263(16):7521–7527. [PubMed]
  • Andres HH, Vogel RS, Tarr GE, Johnson L, Weber WW. Purification, physicochemical, and kinetic properties of liver acetyl-CoA:arylamine N-acetyltransferase from rapid acetylator rabbits. Mol Pharmacol. 1987 Apr;31(4):446–456. [PubMed]
  • Evans DA. N-acetyltransferase. Pharmacol Ther. 1989;42(2):157–234. [PubMed]
  • Blum M, Grant DM, Demierre A, Meyer UA. Nucleotide sequence of a full-length cDNA for arylamine N-acetyltransferase from rabbit liver. Nucleic Acids Res. 1989 May 11;17(9):3589–3589. [PMC free article] [PubMed]
  • Ohsako S, Deguchi T. Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J Biol Chem. 1990 Mar 15;265(8):4630–4634. [PubMed]
  • Blum M, Grant DM, McBride W, Heim M, Meyer UA. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 1990 Apr;9(3):193–203. [PubMed]
  • Kilbane AJ, Petroff T, Weber WW. Kinetics of acetyl CoA: arylamine N-acetyltransferase from rapid and slow acetylator human liver. Drug Metab Dispos. 1991 Mar-Apr;19(2):503–507. [PubMed]
  • Kilbane AJ, Silbart LK, Manis M, Beitins IZ, Weber WW. Human N-acetylation genotype determination with urinary caffeine metabolites. Clin Pharmacol Ther. 1990 Apr;47(4):470–477. [PubMed]
  • Cooper DN, Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. [PubMed]
  • Levy GN, Weber WW. High-performance liquid chromatographic analysis of 32P-postlabeled DNA-aromatic carcinogen adducts. Anal Biochem. 1988 Nov 1;174(2):381–392. [PubMed]
  • McGuire MC, Nogueira CP, Bartels CF, Lightstone H, Hajra A, Van der Spek AF, Lockridge O, La Du BN. Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase. Proc Natl Acad Sci U S A. 1989 Feb;86(3):953–957. [PMC free article] [PubMed]
  • Ohsako S, Ohtomi M, Sakamoto Y, Uyemura K, Deguchi T. Arylamine N-acetyltransferase from chicken liver II. Cloning of cDNA and expression in Chinese hamster ovary cells. J Biol Chem. 1988 Jun 5;263(16):7534–7538. [PubMed]
  • Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. [PubMed]
  • Blum M, Grant DM, Demierre A, Meyer UA. 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):9554–9557. [PMC free article] [PubMed]
  • Deguchi T, Mashimo M, Suzuki T. Correlation between acetylator phenotypes and genotypes of polymorphic arylamine N-acetyltransferase in human liver. J Biol Chem. 1990 Aug 5;265(22):12757–12760. [PubMed]
  • Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980 Apr 11;8(7):1499–1504. [PMC free article] [PubMed]
  • Barker D, Schafer M, White R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell. 1984 Jan;36(1):131–138. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • Gene
    Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • SNP
    SNP
    PMC to SNP links
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...