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Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers.
Pharmacogenet Genomics. 2011 Mar; 21(3):142-51.PG

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.

Authors+Show Affiliations

Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21278620

Citation

Guo, Ren, et al. "Association of GSTM1 Null Polymorphism With Isosorbide-5-mononitrate Cardiovascular Response and Involvement of CGRP in Healthy Chinese Male Volunteers." Pharmacogenetics and Genomics, vol. 21, no. 3, 2011, pp. 142-51.
Guo R, Chen L, Li L, et al. Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers. Pharmacogenet Genomics. 2011;21(3):142-51.
Guo, R., Chen, L., Li, L., Guo, X., Sun, J., Xiong, X. M., Cheng, Z. N., Li, Y. J., & Chen, X. P. (2011). Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers. Pharmacogenetics and Genomics, 21(3), 142-51. https://doi.org/10.1097/FPC.0b013e328343ea0a
Guo R, et al. Association of GSTM1 Null Polymorphism With Isosorbide-5-mononitrate Cardiovascular Response and Involvement of CGRP in Healthy Chinese Male Volunteers. Pharmacogenet Genomics. 2011;21(3):142-51. PubMed PMID: 21278620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers. AU - Guo,Ren, AU - Chen,Lei, AU - Li,Ling, AU - Guo,Xin, AU - Sun,Ji, AU - Xiong,Xiao-Ming, AU - Cheng,Ze-Neng, AU - Li,Yuan-Jian, AU - Chen,Xiao-Ping, PY - 2011/2/1/entrez PY - 2011/2/1/pubmed PY - 2011/5/25/medline SP - 142 EP - 51 JF - Pharmacogenetics and genomics JO - Pharmacogenet Genomics VL - 21 IS - 3 N2 - 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. SN - 1744-6880 UR - https://www.unboundmedicine.com/medline/citation/21278620/Association_of_GSTM1_null_polymorphism_with_isosorbide_5_mononitrate_cardiovascular_response_and_involvement_of_CGRP_in_healthy_Chinese_male_volunteers_ L2 - https://doi.org/10.1097/FPC.0b013e328343ea0a DB - PRIME DP - Unbound Medicine ER -