Arylamine N-acetyltransferase 2 genotype-dependent N-acetylation of isoniazid in cryopreserved human hepatocytes

作     者：Mark A.Doll Raúl A.Salazar-González Srineil Bodduluri David W.Hein 

作者机构：Department of Pharmacology and Toxicology and James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleKY 40202USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2017年第7卷第4期

页      面：517-522页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by National Institutes of Health grants R25-CA134283 and P20-GM113226(USA) 

主　　题：Isoniazid N-Acetyltransferase 2 Acetylation polymorphism Human hepatocytes Genotype Phenotype 

摘      要：Cryopreserved human hepatocytes were used to investigate the role of arylamine N-acetyltransferase 2 (NAT2; EC 2.***.1.5) polymorphism on the N-acetylation of isoniazid (INH). NAT2 genotype was determined by Taqman allelic discrimination assay and INH N-acetylation was measured by high performance liquid chromatography. INH N-acetylation rates in vitro exhibited a robust and highly significant (P0.005) NAT2 phenotype-dependent metabolism. N-acetylation rates in situ were INH concentration- and time-dependent. Following incubation for 24 h with 12.5 or 100 µmol/L INH, acetyl-INH concentrations varied significantly (P = 0.0023 and P = 0.0002) across cryopreserved human hepatocytes samples from rapid, intermediate, and slow acetylators, respectively. The clear association between NAT2 genotype and phenotype supports use of NAT2 genotype to guide INH dosing strategies in the treatment and prevention of tuberculosis.