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.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Guo R,Chen L,Li L,Guo X,Sun J,Xiong XM,Cheng ZN,Li YJ,Chen XPdoi
10.1097/FPC.0b013e328343ea0asubject
Has Abstractpub_date
2011-03-01 00:00:00pages
142-51issue
3eissn
1744-6872issn
1744-6880journal_volume
21pub_type
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e3282f1b2be
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pub_type: 临床试验,杂志文章
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更新日期:2015-04-01 00:00:00
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更新日期:2006-01-01 00:00:00
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更新日期:2007-10-01 00:00:00
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更新日期:2011-09-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
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更新日期:2005-03-01 00:00:00
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更新日期:2014-05-01 00:00:00
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更新日期:2015-01-01 00:00:00
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更新日期:2011-06-01 00:00:00
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