title: Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Ji
authors.initials: J
authors.lastname: Sun
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xiong
authors.forename: Ze-Neng
authors.initials: ZN
authors.lastname: Cheng
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
mesh_terms: D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000502:physiology*; D002319:Cardiovascular System / Q000187:drug effects*; D002681:China; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D015740:Calcitonin Gene-Related Peptide; D005982:Glutathione Transferase; D007548:Isosorbide Dinitrate; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; C096127:ALDH2 protein, human; C030397:isosorbide-5-mononitrate