Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

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.

Figure 1

Purified ALDH2 protein (polyacrylamide gel stained by Coomassie blue). (A) ALDH2 protein purified from human fetal liver. Lane 1, protein from ALDH2*1/1 genotype; lane 2, protein from ALDH2*1/2 genotype; lane 3, molecular weight ladder. (B) Recombinant ALDH2 protein purified via affinity chromatography. Lane 1, molecular weight ladder; lane 2, protein from ALDH2*1/1 genotype; lane 3: protein from ALDH2*2/2 genotype.

Figure 2

Representative Lineweaver-Burk plots for GTN as the variable substrate for the fetal ALDH2*1/1 (A) and ALDH2*1/2 (B) and the recombinant ALDH2*1/1 (C) and ALDH2*2/2 (D) enzymes.

Figure 3

Plasmids containing the inserted ALDH2 cDNA fragment screened by bacterial PCR with universal primer. Lanes 1, 2, and 4, PCR products amplified from bacterial colonies having the recombinant plasmids; lane 3, negative control; lane 5, markers.