Denisenko Natalia P, Sychev Dmitriy A, Sizova Zhanna M, Smirnov Valeriy V, Ryzhikova Kristina A, Sozaeva Zhannet A, Grishina Elena A
Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia.
Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia.
Pharmgenomics Pers Med. 2018 Jun 18;11:107-112. doi: 10.2147/PGPM.S159708. eCollection 2018.
Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation.
The aim of the study was to find if , and genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole.
Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18-91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for (rs776746), C>T in intron (rs35599367), (rs4244285), (rs4986893), and (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy.
We found a connection between genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%-75% percentiles) were 2.84 (1.99-4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86-4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12-2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann-Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (=0.018), and in multiple comparison Kruskal-Wallis test (=0.014).
In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs.
质子泵抑制剂（PPIs）由细胞色素P450代谢。CYP2C19是大多数PPI的主要同工酶，而CYP3A家族是PPI生物转化的次要酶。
本研究旨在探究俄罗斯消化性溃疡患者服用奥美拉唑时， 及 基因型是否与CYP3A和CYP2C19活性相关。
纳入来自俄罗斯莫斯科地区的48例胃或十二指肠溃疡患者（15例男性，33例女性；平均年龄55.0±15.3岁，年龄范围18 - 91岁）。采集外周静脉血用于DNA提取，并对 （rs776746）、内含子 中C>T （rs35599367）、 （rs4244285）、 （rs4986893）和 （rs12248560）进行实时聚合酶链反应多态性分析。患者的尿液样本于上午6点至9点在进食或服药前采集。采用高效液相色谱/质谱法测定尿皮质醇和6β - 羟基皮质醇浓度（用于CYP3A活性）以及奥美拉唑和5 - 羟基奥美拉唑浓度（用于CYP2C19活性）。
我们发现 基因型与CYP3A活性之间存在关联。CYP2C19广泛代谢者（EMs）的6β - 羟基皮质醇/皮质醇中位代谢率（25% - 75%百分位数）为2.84（1.99 - 4.39），CYP2C19超快代谢者（UMs）为2.51（1.86 - 4.73），CYP2C19中间代谢者（IMs）+慢代谢者（PMs）为1.45（1.12 - 2.16）。在CYP2C19 EMs与CYP2C19 IMs + PMs之间（Mann - Whitney检验， = 0.006）、CYP2C19 UMs与CYP2C19 IMs + PMs之间（ = 0.018）以及多重比较的Kruskal - Wallis检验中（ = 0.014），发现CYP3A活性存在统计学显著差异。
在CYP2C19 IMs + PMs中，CYP3A活性显著低于CYP2C19 EMs和UMs。
