Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism*

Okumura, Katsuhiko; Kita, Tomoko; Chikazawa, Shinji; Komada, Fusao; Iwakawa, Seigo; Tanigawara, Yusuke

doi:10.1016/s0009-9236(97)90131-4

Cited by 73 publications

(44 citation statements)

References 32 publications

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“…On the other hand, in the Japanese population, the rapid-type NAT2*4 was present at a higher frequency (51.3%) than the slow-type (NAT2*5B, 1.6%, NAT2*6A, 26.1%, NAT2*6B, 2.2%, NAT2*7A, 1.2%, NAT2*7B, 10.1%) ( Table 2). These frequencies were similar to those reported by Okumura et al (1997) (NAT2*4, 68.6%, NAT2*6A, 19.3%, NAT2*7B, 9.7%, NAT2*5B, 2.4%). We also identified rare NAT2 variants, NAT2*6B and NAT2*7A, which had not been reported before in the Japanese population.…”

Section: Resultssupporting

confidence: 90%

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population

et al. 2001

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By direct sequencing of regions of the human genome containing five genes belonging to the acetyltransferase family, arylamine N-acetyltransferase (NAT1), arylamine N-acetyltransferase (NAT2), arylalkylamine Nacetyltransferase (AANAT), L1 cell adhesion molecule (L1CAM), and the human homolog of Saccharomyces cerevisiae N-acetyltransferase ARD1, we identified 53 single-nucleotide polymorphisms (SNPs) and two insertion/ deletion polymorphisms in 48 healthy Japanese volunteers. NAT1 and NAT2 are so-called drug-metabolizing enzymes. In the NAT1 gene we found two SNPs and a 3-bp insertion/ deletion polymorphism that corresponded to the NAT1*3,

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Section: Resultssupporting

confidence: 90%

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population

et al. 2001

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“…INH, procainamide and some polycyclic amines). 14,[24][25][26][27] To date, a total of 17 mutant alleles have been found in the human NAT2 gene. 28,29) Parkin et al suggested the concordance between the NAT2 genotypes composed of the recently defined 14 mutant alleles and the acetylator phenotype of INH in patients with tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

“…16) Five kinds of polymerase chain reaction (PCR) primers for NAT2 genotyping were synthesized by Rikaken Co. (Nagoya, Japan). 14) All other chemicals were of reagent grades and obtained commercially.…”

Section: Methodsmentioning

confidence: 99%

“…NAT2 Genotyping The NAT2 genotype was defined based on the three point mutations, that is, the wild-type allele (NAT2*4) or three mutant alleles (NAT2*5B, NAT2*6A and NAT2*7B) according to Deguchi and colleagues, [12][13][14] which was diagnosed by the PCR-restriction fragment length polymorphism (RFLP) method using 0.5 ml blood samples.…”

Section: Methodsmentioning

confidence: 99%

“…It was also suggested that the genotyping of these four alleles could predict the acetylator phenotype of procainamide in healthy Japanese subjects. 14) Phenotyping poses some drawbacks and difficulties for routine work because it includes the risk of toxicity and the interruption of drug therapy during test drugs administration. Compared with phenotyping, genotyping is simple and rapid, and subjects are free from the exposure to test drug.…”

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confidence: 99%

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N-Acetyltransferase2 Genotype Correlated with Isoniazid Acetylation in Japanese Tuberculous Patients.

Kita

Tanigawara

Chikazawa

et al. 2001

Biological & Pharmaceutical Bulletin

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In the early 1950s, isoniazid (INH) was developed as chemotherapeutic agent for the treatment of tuberculosis. 2)However, serious side effects including peripheral neuritis and hepatic toxicity were recognized in some patients, despite their dosage being similar to that taken by others. Previous studies indicated that INH was catabolized to inactive Nacetylisoniazid (AcINH) by N-acetyltransferase2 (NAT2) (Fig. 1), and that the interindividual variation of plasma concentration and urinary recovery of INH were characterized by a bimodal or trimodal distribution. 3,4) N-acetylation of INH is reported to be genetically determined in a simple Mendelian fashion, and the frequencies of rapid (and/or intermediate) and slow acetylator of INH is different among racial populations. 5) There have been studies on the relationships between the acetylator phenotype and the efficacy or side effects of INH. The rapid acetylators should take larger doses of INH than slow acetylators, 6) and slow acetylators are at risk of adverse reactions such as peripheral neuritis, 4) hepatic toxicity 4,7) and systemic lupus erythematosus-like syndromes.8,9) These findings strongly suggested the necessity of therapeutic drug monitoring (TDM) in blood or serum to define the most appropriate dosage regimen for each individual. 10,11) Recently, Deguchi and his colleagues defined four NAT2 alleles, the wild-type allele (NAT2*4) and three mutant alleles (NAT2*5B, NAT2*6A and NAT2*7B), which could explain 93-97.5% of the trimodal INH acetylator phenotype among Japanese healthy subjects.12,13) An individual INH N-acetyltransferase2 (NAT2). In the present study, the relationship between the NAT2 genotype and the INH acetylator phenotype was examined in Japanese tuberculous patients and compared with healthy subjects. Subjects were classified according to the genotyping into NAT2*5B (allele4), NAT2*6A (allele3) and NAT2*7B (allele2), using the PCR-RFLP method. Twelve healthy subjects and 7 tuberculous patients participated in the INH acetylator phenotyping study, in which each subject was administered an oral dose of INH, followed by urine sampling for 24 h. Urinary concentrations of INH and N-acetylisoniazid (AcINH) were measured by the HPLC method. The urinary recoveries of INH (% of dose) in healthy subjects in relation to NAT2 genotyping were as follows: 6.4؎2.2 in the homozygotes for the wild-type allele, 10.7؎ 2.2 in the compound heterozygotes for the mutant allele, and 38.6؎6.4 in the homozygotes for the mutant allele. In the patients study, the findings in the corresponding three groups were 4.0؎1.7, 8.8 and 18.3؎9.3. Although no significant difference was found because of the lower systemic exposure of INH in patients compared with healthy subjects, there were differences in the disposition kinetics of INH between subjects with and without mutations in the NAT2 gene, and these findings were observed not only in healthy subjects but also in patients who had comedicated drugs and hepatic dysfunctions. The findings indicated that the metabolism ...

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The Role of Drug Metabolism in Drug Discovery

Bohnert

Gan

2009

Enzyme Inhibition in Drug Discovery and Development

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Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism*

Cited by 73 publications

References 32 publications

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population

N-Acetyltransferase2 Genotype Correlated with Isoniazid Acetylation in Japanese Tuberculous Patients.

The Role of Drug Metabolism in Drug Discovery

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