Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Abstract

Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

Genetics of drug‐induced liver injury: Current knowledge and future prospects

“…Importantly, another allele NAT2*5 , which is rarely seen in East Asians but is common in Europeans and generally considered to be an additional slow acetylator allele, was not a risk factor and may have some protective effects. Some recent in vitro data suggests that the enzyme encoded by NAT2*5 shows higher activity than either *6 or *7 in findings which are consistent with the observations seen in recently in DILI cases 17 . The possibility of dosing with isoniazid based on genotype has been investigated in a clinical trial based in Japan 18 .…”

“…Some recent in vitro data suggests that the enzyme encoded by NAT2*5 shows higher activity than either *6 or *7 in findings which are consistent with the observations seen in recently in DILI cases. 17 The possibility of dosing with isoniazid based on genotype has been investigated in a clinical trial based in Japan. 18 Results of that trial were supportive of this approach but more complex dosing guidelines might be needed for populations where NAT2*5 is common.…”

Relevance of Pharmacogenomics to the Safe Use of Antimicrobials

“…There is a large body of literature suggesting that NAT2 deficiency is associated with an increased risk of developing DILI, though not all reports agree that this is the case (for review, see [ 28 ]). Two recent studies involving genome-wide association approaches suggest that there is a genuine NAT2 association with isoniazid-related DILI [ 29 , 30 ], but one of these [ 30 ] found that only those homozygous for variants associated with strongly impaired enzyme activity [ 31 ] were at risk. This difference in overall conclusions may be due to ethnic differences in NAT2 allele frequencies and reflect the fact that one study was performed in Thailand and the second in Europe and India.…”

Role of N-acetyltransferase 2 gene polymorphism in the human pathology

“…Позже, в 1960 году, на различных этнических группах было показано бимодальное распределение типа инактивации изониазида. Дальнейшие исследования эффективности и безопасности использования изониазида для лечения больных туберкулёзом подтвердили зависимость частоты нейро-и гепатотоксического эффектов препарата от генотипа: медленные ацетиляторы имели более высокие риски развития токсических эффектов при применении изониазида [19][20][21][22][23].…”

“…Последние данные метаанализа показали, что частота развития побочных эффектов выше у лиц с медленным типом ацетилирования в популяции азиатов. Но результаты исследований в популяции европеоидов малочисленны и противоречивы, что не позволяет сделать убедительных выводов о роли полиморфизма NAT2 в развитии побочных эффектов [21,38].…”