Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase.

Published

Journal Article (Review)

The mitochondrial aldehyde dehydrogenase (ALDH2, mtALDH) was recently found to catalyze the reduction of nitroglycerin (glyceryl trinitrate [GTN]) to generate nitrite and 1,2-glyceryl dinitrate. The nitrite generated within the mitochondria is metabolized further to generate nitric oxide (NO)-based bioactivity, by reduction to NO and/or by conversion to S-nitrosothiol, as revealed by a series of biochemical, pharmacologic, and genetic studies. These studies also demonstrated that mechanism-based inactivation of mtALDH is involved in the development of GTN tolerance. In mice in which the mtALDH gene was selectively deleted (mtALDH(-/-)), vascular responsiveness to low but not to high GTN concentrations was eliminated, indicating the existence of an additional mechanism of GTN biotransformation ("high K(m)" pathway). In addition, bioactivation of isosorbide dinitrate/mononitrate vasodilators is independent of mtALDH. Induction of GTN tolerance in vitro in aortae from normal mice selectively affected responsiveness to low doses of GTN, and the remaining responsiveness to high doses of GTN in mtALDH(-/-) vasculature did not exhibit tolerance. These findings suggest strongly that the high K(m) pathway is not involved in the development of GTN tolerance that is mechanism-based. Notably, recent studies indicate that individuals of East Asian origin with the common E487K mutation of mtALDH, which results in decreased mtALDH activity, are significantly less responsive to GTN. These observations in toto provide strong support for the conclusion that mtALDH provides the necessary and sufficient enzymatic mechanism for biotransformation of clinically relevant concentrations of GTN to NO-based vasoactivity and indicate in addition that inactivation of mtALDH plays a significant role in the development of mechanism-based GTN tolerance.

Full Text

Duke Authors

Cited Authors

  • Chen, Z; Stamler, JS

Published Date

  • November 2006

Published In

Volume / Issue

  • 16 / 8

Start / End Page

  • 259 - 265

PubMed ID

  • 17055381

Pubmed Central ID

  • 17055381

International Standard Serial Number (ISSN)

  • 1050-1738

Digital Object Identifier (DOI)

  • 10.1016/j.tcm.2006.05.001

Language

  • eng

Conference Location

  • United States