GSTM1 缺失多态性与异山梨酯-5-单硝酸酯心血管反应的关系及 CGRP 在健康中国男性志愿者中的作用。

Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers.

机构信息

Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan, China.

出版信息

Pharmacogenet Genomics. 2011 Mar;21(3):142-51. doi: 10.1097/FPC.0b013e328343ea0a.

DOI:10.1097/FPC.0b013e328343ea0a

PMID:21278620

Abstract

OBJECTIVES

To determine whether functional polymorphisms of glutathione S-transferase μ type 1 (GSTM1) and aldehyde dehydrogenase-2 (ALDH2) affect the isosorbide 5-mononitrate (IS-5-MN) response, and the role of the calcitonin gene-related peptide (CGRP) in IS-5-MN response in healthy volunteers.

METHODS

A two-phase, placebo-controlled study was carried out in 24 healthy Chinese volunteers with their ALDH2 and GSTM1 genotypes known. During each phase, either 20-mg IS-5-MN tablet or placebo was orally administered; blood pressure (BP), heart rate, and plasma concentration of CGRP was determined before and at several time points after drug administration. Pharmacokinetic parameters of IS-5-MN were determined.

RESULTS

GSTM1 null individuals showed significantly lower systolic BP (SBP) and diastolic BP (DBP), and higher degree of decreases in SBP (ΔSBP) and DBP (ΔDBP) after IS-5-MN administration. GSTM1 null individuals showed significantly decreased IS-5-MN area under the plasma concentration-time curve than GSTM1 wild-type individuals (P<0.05). Plasma concentration of CGRP was increased significantly at 0.5 (P<0.01), 1 (P<0.05), and 2 h (P<0.05) after IS-5-MN administration in GSTM1 null individuals but not wild-type individuals. GSTM1 null individuals also showed significantly higher degree of percentage increase in the plasma concentration of CGRP than GSTM1 wild-type individuals at 1 h after IS-5-MN administration (P<0.05). IS-5-MN upregulated CGRP I and CGRP II mRNA expressions in cultured peripheral blood mononuclear cells, and the IS-5-MN-induced CGRP II mRNA expression was inhibited by GSTs inhibitor, ethacrynic acid. No difference in the IS-5-MN response was observed between ALDH2 genotypes.

CONCLUSION

We suggest that GSTM1, but not ALDH2, may interfere with the bioactivation of IS-5-MN, and CGRP contributes to the IS-5-MN response in a GSTM1 genotype-dependent manner.

摘要

目的

确定谷胱甘肽 S-转移酶 μ 型 1（GSTM1）和醛脱氢酶-2（ALDH2）的功能多态性是否影响异山梨醇 5-单硝酸酯（IS-5-MN）的反应，以及降钙素基因相关肽（CGRP）在健康志愿者中对 IS-5-MN 反应的作用。

方法

在已知其 ALDH2 和 GSTM1 基因型的 24 名健康中国志愿者中进行了两阶段、安慰剂对照研究。在每个阶段，志愿者分别口服 20mg 的 IS-5-MN 片剂或安慰剂；在给药前和给药后多个时间点测定血压（BP）、心率和血浆 CGRP 浓度。测定 IS-5-MN 的药代动力学参数。

结果

GSTM1 缺失个体在服用 IS-5-MN 后，收缩压（SBP）和舒张压（DBP）明显降低，SBP（ΔSBP）和 DBP（ΔDBP）下降幅度更大。与 GSTM1 野生型个体相比，GSTM1 缺失个体的 IS-5-MN 血浆浓度-时间曲线下面积明显降低（P<0.05）。GSTM1 缺失个体在服用 IS-5-MN 后 0.5（P<0.01）、1（P<0.05）和 2（P<0.05）h 时，血浆 CGRP 浓度明显升高，但 GSTM1 野生型个体无此变化。与 GSTM1 野生型个体相比，GSTM1 缺失个体在服用 IS-5-MN 后 1h 时，血浆 CGRP 浓度的百分比增加程度明显更高（P<0.05）。IS-5-MN 可上调培养外周血单核细胞中 CGRP I 和 CGRP II mRNA 的表达，GSTs 抑制剂乙二醛酸可抑制 IS-5-MN 诱导的 CGRP II mRNA 表达。ALDH2 基因型对 IS-5-MN 反应无差异。