Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin.
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.
Li
Yifeng
Y
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
Zhang
Dandan
D
Jin
Wei
W
Shao
Chunhong
C
Yan
Pengrong
P
Xu
Congjian
C
Sheng
Haihui
H
Liu
Yan
Y
Yu
Jinde
J
Xie
Yuying
Y
Zhao
Yingnan
Y
Lu
Daru
D
Nebert
Daniel W
DW
Harrison
Donald C
DC
Huang
Wei
W
Jin
Li
L
D000286:Administration, Sublingual; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002681:China; D003327:Coronary Disease / Q000188:drug therapy; D005260:Female; D005333:Fetus / Q000033:anatomy & histology / Q000201:enzymology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000378:metabolism* / Q000627:therapeutic use; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D011994:Recombinant Proteins; D018698:Glutamic Acid; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin