Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity.
Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity.
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CYP2C:TG 单倍型对 CYP2C19 体内底物清除率、蛋白质含量和体外活性的影响。
DOI：
10.1002/cpt.3012
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发表时间：
2023
影响因子：
6.7
通讯作者：
Gaedigk,Andrea
中科院分区：
文献类型：
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作者：
Zubiaur,Pablo;Soria-Chacartegui,Paula;Boone,ErinC;Prasad,Bhagwat;Dinh,Jean;Wang,WendyY;Zugbi,Santiago;Rodríguez-Lopez,Andrea;González-Iglesias,Eva;Leeder,JSteven;Abad-Santos,Francisco;Gaedigk,Andrea
一种由两个非编码变体 CYP2C18NM_000772.3:c.*31T (rs2860840) 和 NM_000772.2:c.819+2182G (rs11188059) 组成的新型单倍型，称为“CYP2C:TG”，最近与各种 CYP2C19 底物的超快代谢相关。由于这种效应的潜在机制和临床相关性仍不确定，我们分析了现有的体内和体外数据以确定 CYP2C:TG 单倍型效应的程度。我们在 222 名接受这六种药物之一的健康志愿者中评估了 CYP2C19 底物（包括西酞普兰、舍曲林、伏立康唑、奥美拉唑、泮托拉唑和雷贝拉唑）的药代动力学变异性。我们还利用 N-去甲基托莫西汀的形成确定了它对 135 个人类肝组织样本中 CYP2C8、CYP2C9、CYP2C18 和 CYP2C19 蛋白丰度的影响，以及对 CYP2C18/CYP2C19 体外活性的影响。根据CYP2C:TG单倍型或CYP2C19*1+TG等位基因（即，含有CYP2C:TG单倍型的CYP2C19等位基因）没有观察到影响。相反，与正常代谢者、快速代谢者（即CYP2C19*1/*17）和超快速代谢者相比，CYP2C19中间代谢者（例如CYP2C19*1/*2）和弱代谢者（例如CYP2C19*2/*2）表现出体内暴露量显着较高，人肝微粒体中CYP2C19蛋白丰度较低，体外活性较低（即 CYP2C19*17/*17）。此外，与快速代谢者和正常代谢者相比，在超快速代谢者中观察到暴露量较低的趋势。此外，当CYP2C19*17等位基因存在时，CYP2C18蛋白丰度增加，表明CYP2C19的遗传变异可能与某些药物的整体代谢相关，不仅调节其表达水平，而且还调节CYP2C18的表达水平。考虑到所有可用数据，我们得出结论，没有足够的证据支持临床 CYP2C:TG 测试为药物治疗提供信息。
A novel haplotype composed of two non‐coding variants,CYP2C18NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as “CYP2C:TG,” was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existingin vivoandin vitrodata to determine the magnitude of theCYP2C:TGhaplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activityin vitrousing N‐desmethyl atomoxetine formation. No effects were observed according toCYP2C:TGhaplotype or toCYP2C19*1+TGalleles (i.e.,CYP2C19alleles containing theCYP2C:TGhaplotype). In contrast, CYP2C19 intermediate (e.g.,CYP2C19*1/*2) and poor metabolizers (e.g.,CYP2C19*2/*2) showed significantly higher exposurein vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activityin vitrocompared with normal, rapid (i.e.,CYP2C19*1/*17), and ultrarapid metabolizers (i.e.,CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when theCYP2C19*17allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation inCYP2C19may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinicalCYP2C:TGtesting to inform drug therapy.
由流式分选染色体构建的人类 8 号染色体粘粒文库的表征。
DOI：
10.1159/000133260
发表时间：
1992
期刊：
Cytogenetics and cell genetics
影响因子：
--
作者：
S. Wood;M. Schertzer;H. Drabkin;D. Patterson;J. Longmire;L. Deaven
通讯作者：
L. Deaven