• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. Sep 1995; 57(3): 581–592.
PMCID: PMC1801274

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity.

Abstract

The polymorphic arylamine N-acetyltransferase (NAT2; EC 2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had a genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2*4/*4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles *5A, *5C, and *13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of *6A, *7B, and *13 alleles than the group of *5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations.

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 (1.9M), 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

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Agúndez JA, Martínez C, Olivera M, Ledesma MC, Ladero JM, Benítez J. Molecular analysis of the arylamine N-acetyltransferase polymorphism in a Spanish population. Clin Pharmacol Ther. 1994 Aug;56(2):202–209. [PubMed]
  • Bechtel YC, Bonaiti-Pellie C, Poisson N, Magnette J, Bechtel PR. A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther. 1993 Aug;54(2):134–141. [PubMed]
  • Bell DA, Taylor JA, Butler MA, Stephens EA, Wiest J, Brubaker LH, Kadlubar FF, Lucier GW. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. Carcinogenesis. 1993 Aug;14(8):1689–1692. [PubMed]
  • Blum M, Demierre A, Grant DM, Heim M, Meyer UA. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5237–5241. [PMC free article] [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]
  • Cribb AE, Isbrucker R, Levatte T, Tsui B, Gillespie CT, Renton KW. Acetylator phenotyping: the urinary caffeine metabolite ratio in slow acetylators correlates with a marker of systemic NAT1 activity. Pharmacogenetics. 1994 Jun;4(3):166–170. [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]
  • EVANS DA, WHITE TA. HUMAN ACETYLATION POLYMORPHISM. J Lab Clin Med. 1964 Mar;63:394–403. [PubMed]
  • Ferguson RJ, Doll MA, Rustan TD, Gray K, Hein DW. Cloning, expression, and functional characterization of two mutant (NAT2(191) and NAT2(341/803)) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Drug Metab Dispos. 1994 May-Jun;22(3):371–376. [PubMed]
  • Graf T, Broly F, Hoffmann F, Probst M, Meyer UA, Howald H. Prediction of phenotype for acetylation and for debrisoquine hydroxylation by DNA-tests in healthy human volunteers. Eur J Clin Pharmacol. 1992;43(4):399–403. [PubMed]
  • Grant DM, Tang BK, Kalow W. A simple test for acetylator phenotype using caffeine. Br J Clin Pharmacol. 1984 Apr;17(4):459–464. [PMC free article] [PubMed]
  • Grant DM, Blum M, Demierre A, Meyer UA. Nucleotide sequence of an intronless gene for a human arylamine N-acetyltransferase related to polymorphic drug acetylation. Nucleic Acids Res. 1989 May 25;17(10):3978–3978. [PMC free article] [PubMed]
  • Hashiguchi M, Ebihara A. Acetylation polymorphism of caffeine in a Japanese population. Clin Pharmacol Ther. 1992 Sep;52(3):274–276. [PubMed]
  • Hayes RB, Bi W, Rothman N, Broly F, Caporaso N, Feng P, You X, Yin S, Woosley RL, Meyer UA. N-acetylation phenotype and genotype and risk of bladder cancer in benzidine-exposed workers. Carcinogenesis. 1993 Apr;14(4):675–678. [PubMed]
  • Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, Grant DM. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis. 1993 Aug;14(8):1633–1638. [PubMed]
  • Hein DW, Ferguson RJ, Doll MA, Rustan TD, Gray K. Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes. Hum Mol Genet. 1994 May;3(5):729–734. [PubMed]
  • Hickman D, Sim E. N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. Biochem Pharmacol. 1991 Aug 8;42(5):1007–1014. [PubMed]
  • Hickman D, Risch A, Buckle V, Spurr NK, Jeremiah SJ, McCarthy A, Sim E. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem J. 1994 Feb 1;297(Pt 3):441–445. [PMC free article] [PubMed]
  • Lin HJ, Han CY, Lin BK, Hardy S. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology. Am J Hum Genet. 1993 Apr;52(4):827–834. [PMC free article] [PubMed]
  • Lin HJ, Han CY, Lin BK, Hardy S. Ethnic distribution of slow acetylator mutations in the polymorphic N-acetyltransferase (NAT2) gene. Pharmacogenetics. 1994 Jun;4(3):125–134. [PubMed]
  • Mashimo M, Suzuki T, Abe M, Deguchi T. Molecular genotyping of N-acetylation polymorphism to predict phenotype. Hum Genet. 1992 Sep-Oct;90(1-2):139–143. [PubMed]
  • Mrozikiewicz PM, Drakoulis N, Roots I. Polymorphic arylamine N-acetyltransferase (NAT2) genes in children with insulin-dependent diabetes mellitus. Clin Pharmacol Ther. 1994 Dec;56(6 Pt 1):626–634. [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]
  • Relling MV, Lin JS, Ayers GD, Evans WE. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther. 1992 Dec;52(6):643–658. [PubMed]
  • Rothman N, Hayes RB, Bi W, Caporaso N, Broly F, Woosley RL, Yin S, Feng P, You X, Meyer UA. Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese males. Pharmacogenetics. 1993 Oct;3(5):250–255. [PubMed]
  • Vatsis KP, Martell KJ, Weber WW. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6333–6337. [PMC free article] [PubMed]
  • Vatsis KP, Weber WW, Bell DA, Dupret JM, Evans DA, Grant DM, Hein DW, Lin HJ, Meyer UA, Relling MV, et al. Nomenclature for N-acetyltransferases. Pharmacogenetics. 1995 Feb;5(1):1–17. [PubMed]
  • Weber WW, Vatsis KP. Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics. 1993 Aug;3(4):209–212. [PubMed]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...