Doll Mark A, Salazar-González Raúl A, Bodduluri Srineil, Hein David W
Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Acta Pharm Sin B. 2017 Jul;7(4):517-522. doi: 10.1016/j.apsb.2017.05.003. Epub 2017 Jun 7.
Cryopreserved human hepatocytes were used to investigate the role of arylamine -acetyltransferase 2 (NAT2; EC 2.3.1.5) polymorphism on the -acetylation of isoniazid (INH). genotype was determined by Taqman allelic discrimination assay and INH -acetylation was measured by high performance liquid chromatography. INH -acetylation rates exhibited a robust and highly significant (<0.005) NAT2 phenotype-dependent metabolism. -acetylation rates were INH concentration- and time-dependent. Following incubation for 24 h with 12.5 or 100 µmol/L INH, acetyl-INH concentrations varied significantly ( = 0.0023 and = 0.0002) across cryopreserved human hepatocytes samples from rapid, intermediate, and slow acetylators, respectively. The clear association between genotype and phenotype supports use of genotype to guide INH dosing strategies in the treatment and prevention of tuberculosis.
使用冷冻保存的人肝细胞来研究芳胺 - 乙酰转移酶2（NAT2；EC 2.3.1.5）基因多态性对异烟肼（INH）乙酰化作用的影响。通过Taqman等位基因鉴别分析确定基因型，并通过高效液相色谱法测量INH的乙酰化作用。INH乙酰化率表现出强烈且高度显著（<0.005）的NAT2表型依赖性代谢。乙酰化率呈INH浓度和时间依赖性。在用12.5或100 µmol/L INH孵育24小时后，乙酰-INH浓度在来自快速、中间和慢速乙酰化者的冷冻保存人肝细胞样本中分别有显著差异（P = 0.0023和P = 0.0002）。基因型与表型之间的明确关联支持使用基因型来指导治疗和预防结核病时的INH给药策略。
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