An essential role for mitochondrial aldehyde dehydrogenase in nitroglyc­erin bioactivation.

Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T, Kitagawa K, Nakayama KI, Hess DT, Stamler JS. Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12159-64. Epub 2005 Aug 15.

Reviewer: Theodore A. Alston, MD, PhD
Assistant Professor
Harvard Medical School

Abstract: Nitroglycerin (TNG) is believed to dilate blood vessels be-cause the drug, a nitrate ester (R-ONO₂), is converted to nitric oxide (NO). The chemical transformation of a nitrate to NO requires three electrons to come from some reducing agents somewhere. However, the biological reducing system for conversion of TNG to NO has been mysterious. The Stamler group argues compellingly that the reductive bioactivation of TNG occurs within mitochondria. Curiously, one of the important enzymes is mitochondrial aldehyde dehydrogenase, an enzyme which participates in the metabolism of ethanol.

A strain of mice was caused to genetically lack the dehydrogenase. Knocking out the dehydrogenase caused the mice to be resistant to the hypotensive effect of intravenous TNG. The knockout did not reduce sen-sitivity to nitroprusside, which is expected to have a different mechanism for its conversion to NO. In vitro, aortic segments from knockout mice were resistant to dilation by TNG. TNG is converted to NO which dilates blood vessels through activation of vascular smooth muscle guanylate cyclase. Accordingly, aortic segments from knockout mice generated lower levels of intracellular cyclic-GMP upon exposure to TNG.

Mitochondria were isolated from disrupted mouse liver cells and used in experiments in vitro. Interesting results were found with layers of rat lung fibroblasts, which generate cyclic-GMP in response to NO but generate very little cyclic-GMP in response to TNG. Exposure of the fibroblasts to TNG alone, or to mitochondria without TNG, elicited little cyclic-GMP. Together, mitochondria plus TNG elicited much cyclic-GMP in the fibroblasts. Cyclic-GMP production was blocked by hemoglobin, which destroys NO. It was also blocked by genetic deletion of the mitochondrial dehydrogenase or by inhibition of the dehydrogenase with choral hydrate.

TNG induces TNG tolerance. Aortic segments from TNG-tolerant mice behave similarly to segments lacking the mitochondrial aldehydede hydrogenase or having the dehydrogenase inhibited by choral hydrate.

Comments: The chemist Ascanio Sobrero synthesized nitroglycerin in 1847. He noted that a trace amount of the vasodilator causes headaches. Alfred Nobel "tamed" TNG into dynamite. That is, he showed that spontaneous explosions of TNG were prevented by absorbing the liquid onto porous solids. Given non-exploding products, William Murrell described treatment of angina pectoris with TNG in 1876. Furchgott, Ignarro, and Murad shared the 1998 Nobel Prize in large part for showing that TNG is a vasodilator because it is converted to the same NO that is normally presented to vascular smooth muscle by endothelium. Yet, the molecular mechanism for the 3-electron reduction of TNG to NO remains mysterious.

Part of the mystery seems clarified. Mitochondria are full of reduction-oxidation enzymes, and those cellular organelles are now shown capable of transforming TNG into a diffusible substance that raises cyclic-GMP and dilates blood vessels and is scavenged by hemoglobin. One of the mitochondrial enzymes important in this regard is aldehyde dehydrogenase. That enzyme is genetically impaired in many individuals who tolerate ethanol poorly. The enzyme is subject to pharmacological inhibition by chloral hydrate and other drugs carrying an antabuse-like side-effect. Presumably, the ability of the dehydrogenase to react with TNG is competitively inhibited during the participation of the enzyme in the metabolism of ethanol.

The enzyme loses its ability to participate in the bioactivation of TNG upon prior exposure to TNG, and the Stamler group thus point to mito-chondrial aldehyde dehydrogenase as the protein most responsible for TNG-induced tolerance to TNG.

It is puzzling that the dehydrogenase catalyzes the oxidation of acetaldehyde, but it participates in the reduction of TNG. The enzyme carries a critical active-site sulfhydryl group (R-SH) that normally attaches covalently to acetaldehyde during the dehydrogenation reaction. Perhaps the sulfhydryl group is a TNG reductant. Maybe NADH is the reductant. NADH is expected to carry only two electrons, and 3-electron reactions are expected by chemists to proceed via more than one step. The three little electrons for venerable TNG are not yet fully accounted.

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