Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers
Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers
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DOI：
10.1097/fpc.0b013e328343ea0a
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发表时间：
2011-03
影响因子：
2.6
通讯作者：
Ren Guo;Lei Chen;Ling-Fang Li;Xin Guo;Ji Sun;X. Xiong;Ze-Neng Cheng;Yuan‐jian Li;Xiaoping Chen
中科院分区：
文献类型：
--
作者：
Ren Guo;Lei Chen;Ling-Fang Li;Xin Guo;Ji Sun;X. Xiong;Ze-Neng Cheng;Yuan‐jian Li;Xiaoping Chen
Objectives To determine whether functional polymorphisms of glutathione S-transferase 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 (&Dgr;SBP) and DBP (&Dgr;DBP) 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.
