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Studies on the urinary assay of CYP-mediated endogenous corticosteroid metabolites with a LC-MS method

LC-MS 法测定尿液中 CYP 介导的内源性皮质类固醇代谢物的研究

基本信息

批准号：
18590542
负责人：
ECHIZEN Hirotoshi
金额：
$ 2.79万
依托单位：
Meiji Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2009
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590542/
关键词：
薬物代謝個人差ステロイドホルモン LC-MS ステロイド

项目摘要

Interindividual variability of the drug metabolizing enzyme activity is associated with those of drug responses and adverse drug reactions. Recent advances in molecular biology have made it possible to account for a part of interindividual variability of important drug metabolizing enzymes, particularly cytochrome P-450s (CYPs) in the light of pharmacogenomics. Nevertheless, it has also become evident that a large interindividual variability still exists in subjects or patients having none of the previously known loss-of-function SNPs in the respective CYP isoforms. Thus, there is a surge of interest to reappraise for assessing CYP isoform activity as phenotype individually. We have previously reported that in vivo CYP3A4 activity may be assessed by urinary excretion of 6β-hydroxycortisol, a CYP3A4 metabolite of adrenal cortisol, or its metabolic ratio of cortisol. In order to extend this idea to other steroid hormones which are thought to be metabolized by different CYP isoforms, we aimed to establish a comprehensive assay method using HPLC-UV and LC-MS. We have established a simultaneous assay method for urinary 2- and 4-hydroxyestradiol and 17-hydroxyprogesterone, of which metabolism are associated with CYP1A2 and CYP2C19, respectively, with an HPLC-UV method as a preliminary study. We found that there is a large interindividual variability in the urinary excretion of those sex steroid metabolites, indicating that there is a good chance to measure interindividual variability of the these CYP activities. Then, we advanced our study to establish a LC-MS method. We consider that this method would be useful for a population study where a large number of clinical samples are to be assayed.

药物代谢酶活性的个体间变异性与药物反应和药物不良反应的个体间变异性相关。分子生物学的最新进展使人们有可能解释一部分重要药物代谢酶的个体间变异性，特别是根据药物基因组学的细胞色素P-450（CYP）。然而，也已经变得明显的是，在各个SNP亚型中没有先前已知的功能丧失SNP的受试者或患者中仍然存在大的个体间变异性。因此，有兴趣重新评估评估作为个体表型的β亚型活性。我们之前曾报道过，体内CYP 3A 4活性可以通过6β-羟基皮质醇（肾上腺皮质醇的CYP 3A 4代谢物）的尿液排泄或其皮质醇的代谢比来评估。为了将这一观点推广到其他被认为是由不同的β-羟孕酮异构体代谢的类固醇激素，我们旨在建立一种综合的HPLC-UV和LC-MS测定方法。我们建立了同时测定尿中2-和4-羟孕酮和17-羟孕酮的方法，它们分别与CYP 1A 2和CYP 2C 19代谢相关，采用HPLC-UV法进行初步研究。我们发现，这些性类固醇代谢物的尿排泄存在很大的个体间变异性，这表明有很好的机会来测量这些类固醇活性的个体间变异性。在此基础上，我们进一步研究建立了LC-MS方法。我们认为，这种方法将是有用的人口研究，其中大量的临床样本进行分析。