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.
Highlights
N-acetyltransferase 2 (NAT2) is responsible for N-acetylation of aromatic amines and hydrazine derivatives
Many studies have reported strong associations of each NAT2 genotype, such as NAT2∗6A/∗6A, with the risk of anti-TB drug-induced liver injury (ATDILI) (Suvichapanich et al, 2018; Nicoletti et al, 2020; Yuliwulandari et al, 2021), little information is available regarding the associations between NAT2 genotype and the risk of the adverse reactions induced by other NAT2 substrate drugs
The AFR population consisted of African Caribbeans in Barbados (ACB); Americans of African ancestry in the southwest United States (ASW); Esan in Nigeria (ESN); Luhya in Webuye, Kenya (LWK); Mandinka in the Gambia (MAG); Mende in Sierra Leone (MSL); and Yoruba in Ibadan, Nigeria (YRI)
Summary
N-acetyltransferase 2 (NAT2) is responsible for N-acetylation of aromatic amines and hydrazine derivatives. Because patients with TB harboring NAT2∗5, ∗6, and ∗7 show much slower N-acetylation than patients homozygous for NAT2∗4 (Mthiyane et al, 2020), accumulation of INH and hydrazine occurs in SAs, leading to a higher risk of liver injury (An et al, 2018; Brewer et al, 2019) These phenotypes may be the most efficient pharmacogenomics biomarkers for predicting the risk of ATDILI (Azuma et al, 2013; Mushiroda et al, 2016; Wattanapokayakit et al, 2016; Yuliwulandari et al, 2016; Suvichapanich et al, 2019) and may lead to identification of a cost-effective treatment for TB (Rens et al, 2020). The substrate specificity of N-acetylation with relation to categorization of NAT2 genotypes into phenotypes has not been reported (Zang et al, 2007)
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