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Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin.
J Clin Invest. 2006 Feb; 116(2):506-11.JCI

Abstract

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2--resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes--is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

Authors+Show Affiliations

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People's Republic of 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 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)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16440063

Citation

Li, Yifeng, et al. "Mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) Glu504Lys Polymorphism Contributes to the Variation in Efficacy of Sublingual Nitroglycerin." The Journal of Clinical Investigation, vol. 116, no. 2, 2006, pp. 506-11.
Li Y, Zhang D, Jin W, et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006;116(2):506-11.
Li, Y., Zhang, D., Jin, W., Shao, C., Yan, P., Xu, C., Sheng, H., Liu, Y., Yu, J., Xie, Y., Zhao, Y., Lu, D., Nebert, D. W., Harrison, D. C., Huang, W., & Jin, L. (2006). Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. The Journal of Clinical Investigation, 116(2), 506-11.
Li Y, et al. Mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) Glu504Lys Polymorphism Contributes to the Variation in Efficacy of Sublingual Nitroglycerin. J Clin Invest. 2006;116(2):506-11. PubMed PMID: 16440063.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. AU - Li,Yifeng, AU - Zhang,Dandan, AU - Jin,Wei, AU - Shao,Chunhong, AU - Yan,Pengrong, AU - Xu,Congjian, AU - Sheng,Haihui, AU - Liu,Yan, AU - Yu,Jinde, AU - Xie,Yuying, AU - Zhao,Yingnan, AU - Lu,Daru, AU - Nebert,Daniel W, AU - Harrison,Donald C, AU - Huang,Wei, AU - Jin,Li, Y1 - 2006/01/26/ PY - 2005/08/11/received PY - 2005/11/15/accepted PY - 2006/1/28/pubmed PY - 2006/3/24/medline PY - 2006/1/28/entrez SP - 506 EP - 11 JF - The Journal of clinical investigation JO - J Clin Invest VL - 116 IS - 2 N2 - Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2--resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes--is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/16440063/Mitochondrial_aldehyde_dehydrogenase_2__ALDH2__Glu504Lys_polymorphism_contributes_to_the_variation_in_efficacy_of_sublingual_nitroglycerin_ DB - PRIME DP - Unbound Medicine ER -