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

Journal Article · Mon Jul 15 00:00:00 EDT 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.14.6333· OSTI ID:5933341

Vatsis, K P; Martell, K J; Weber, W W ^[1]

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1. Univ. of Michigan, Ann Arbor (United States)

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 variation. Two highly homologous human genes for N-acetyltransferase 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 (coden 94) and a separate G {r arrow} 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. The results show conclusively that the genetically variant NAT is encoded by NAT2.

• OSTI ID: 5933341
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:14; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
AMINES
ACETYLATION
DNA
AUTORADIOGRAPHY
LIVER
METABOLISM
DNA BASE TRANSITIONS
GENE MUTATIONS
GENOTYPE
OLIGONUCLEOTIDES
PHOSPHORUS 32
TRANSFERASES
ACYLATION
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
CHEMICAL REACTIONS
DAYS LIVING RADIOISOTOPES
DIGESTIVE SYSTEM
ENZYMES
GLANDS
ISOTOPES
LIGHT NUCLEI
MUTATIONS
NUCLEI
NUCLEIC ACIDS
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANS
PHOSPHORUS ISOTOPES
PROTEINS
RADIOISOTOPES
550201* - Biochemistry- Tracer Techniques