Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (Y.U., M.I., A.A., M.S.); Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan(S.U., K.B., N.M., H.Y.); and School of Veterinary Medicine, Kitasato University, Aomori, Japan (H.K.)
Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (Y.U., M.I., A.A., M.S.); Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan(S.U., K.B., N.M., H.Y.); and School of Veterinary Medicine, Kitasato University, Aomori, Japan (H.K.).
Drug Metab Dispos. 2022 Nov;50(11):1429-1433. doi: 10.1124/dmd.122.000919. Epub 2022 Jun 29.
Arylamine -acetyltransferases (NATs) are drug-metabolizing enzymes that are essential for the metabolism of endogenous substrates and xenobiotics. The molecular characteristics of NATs have been extensively investigated in humans but remain to be investigated in common marmosets and pigs, animal species that are often used in drug metabolism studies. In this study, marmoset NAT1 and pig NAT1 cDNAs were isolated from liver samples and were characterized by molecular analyses and drug-metabolism assays. These genes were intronless and formed gene clusters with one other gene in the genome, just as human genes do. Marmoset NAT1 and pig NAT1 amino acid sequences showed high sequence identities (94% and 85%, respectively) to human NAT1. Phylogenetic analysis indicated that marmoset NAT1 and pig NAT1 were more closely clustered with human NATs than with rat or mouse NATs. Marmoset NAT1 and pig NAT1 mRNAs were expressed in all the tissue types analyzed, with the expression levels being highest in the small intestine. Metabolic assays using recombinant proteins found that marmoset NAT1 and pig NAT1 metabolized human NAT substrates -aminobenzoic acid, 2-aminofluorene, sulfamethazine, and isoniazid. Marmoset NAT1 and pig NAT1 substantially acetylated -aminobenzoic acid and 2-aminofluorene relevant human NAT1, but their activities were lower toward sulfamethazine and isoniazid than those of the relevant human NAT2. Therefore, marmoset and pig NATs are functional enzymes with molecular similarities to human NAT1, but their substrate specificities, while similar to human NAT1, differ somewhat from human NAT2. SIGNIFICANCE STATEMENT: Marmoset -acetyltransferase NAT1 and pig NAT1 were identified and showed high sequence identities to human NAT1. These NAT mRNAs were expressed in various tissues. Marmoset and pig NAT1s acetylated typical human NAT substrates, although their substrate specificities differed somewhat from human NAT2. Marmoset NAT1 and pig NAT1 have similarities with human NAT1 in terms of molecular and enzymatic characteristics.
芳香胺 -N- 乙酰基转移酶（NATs）是参与内源性底物和外源性毒物代谢的药物代谢酶。NATs 的分子特征已在人类中得到广泛研究，但在常见的绒猴和猪中仍有待研究，这两种动物通常用于药物代谢研究。在这项研究中，从肝脏样本中分离出绒猴 NAT1 和猪 NAT1 cDNA，并通过分子分析和药物代谢测定对其进行了表征。这些基因无内含子，与基因组中的另一个基因一起形成基因簇，就像人类基因一样。绒猴 NAT1 和猪 NAT1 氨基酸序列与人类 NAT1 具有高度的序列同一性（分别为 94%和 85%）。系统发育分析表明，绒猴 NAT1 和猪 NAT1 与人类 NATs 的聚类比与大鼠或小鼠 NATs 的聚类更为密切。绒猴 NAT1 和猪 NAT1 mRNA 在分析的所有组织类型中均有表达，其中小肠中的表达水平最高。使用重组蛋白进行的代谢测定发现，绒猴 NAT1 和猪 NAT1 代谢人类 NAT 底物 -氨基苯甲酸、2-氨基芴、磺胺甲噁唑和异烟肼。绒猴 NAT1 和猪 NAT1 可显著乙酰化 -氨基苯甲酸和 2-氨基芴，与人类 NAT1 相关，但它们对磺胺甲噁唑和异烟肼的活性低于相关的人类 NAT2。因此，绒猴和猪 NAT 是具有与人类 NAT1 分子相似性的功能性酶，但它们的底物特异性与人类 NAT1 相似，但与人类 NAT2 略有不同。意义陈述：鉴定出绒猴 -乙酰转移酶 NAT1 和猪 NAT1，并与人类 NAT1 具有高度的序列同一性。这些 NAT mRNA 在各种组织中表达。绒猴和猪 NAT1 乙酰化典型的人类 NAT 底物，尽管它们的底物特异性与人类 NAT2 略有不同。在分子和酶学特征方面，绒猴 NAT1 和猪 NAT1 与人类 NAT1 具有相似性。
