Mitochondrial Aldehyde Dehydrogenase Gene In Multi-state E487k On The Efficacy And Metabolism Of Nitroglycerin

Nitroglycerin (NTG) has been very widely used for the management of coronary heart disease, since its first clinical application in 1876. The sublingual administration of nitroglycerin is the standard treatment for acute attacks of angina pectoris, and the symptom is usually relieved within 5 to 10 minutes.Recently, it has been shown that the Mitochondrial aldehyde dehydrogenase is responsible for the bioactivation of nitroglycerin prior to the release of NO, which is a strong vasodilator. Mitochondrial aldehyde dehydrogenase, a member of a superfamily of NAD(P)(+)-dependent enzymes has both dehydrogenase activity and eaterase activity, which can catalyze the biotransformation of nitroglycerin. A functional single nucleotide polymorphism (SNP) in exon 12, which leads to a replacement of glutamate by lysine at position 487 virtually eliminating its ability to clear acetaldehyde in the carriers, has high prevalence in Asian populations including Chinese with the allelic frequency around 30%. The fact that acetaldehyde and nitroglycerin can be the compitive inhibitor reciprocally and the mutant enzyme also lose esterase activity makes us speculate that this olymorphism can affect the biotransformation of nitroglycerin in vivo.80 stable angina pectoris patients were recruited from total 576 angiographically defined coronary heart disease patients according to the inclusion criteria, and interindividual variation of the efficacy of sublingual nitroglycerin is significantly associated with this mitochondrial aldehyde dehydrogenase polymorphism in Chinese (X² = 7.59, P < 0.01). Further, all three genotype enzymes were obtained by either purification from human fetus livers or expression in the Bac-to-Bac baculovirus system. The kinetic properties of each genotype was characterized by the thin layer chromatography and liquid scintillation spectrometry with the [2-¹⁴C] nitroglycerin as the substrate, The catalytic efficiency of mitochondrial aldehyde dehydrogenase (Vmax/Km) of different genotype differs significantly (9 and 11 times respectively). Furthermore, the molecular mechanism underlying the different catalytic efficiency was discussed with the use of simulation software-insight II. Finally, we enrolled 20volunteers of three genotypes (wild-type 10 individuals; heterozygote 5 individuals; mutant homozygotes 5 individuals), After taking nitroglycerin, the pharmacokinetics curve was obtained with the use of gas chromatography. No difference was found with respect to half-life and AUC etc. These observation suggest that the presence of the A allele is at least partially but significantly responsible for the failure or reduced response to nitroglycerin; therefore, genetic factor should be involved in the consideration of the administration of nitroglycerin especially in oriental populations.