Organic nitrate metabolism and action: toward a unifying hypothesis and the future-a dedication to Professor Leslie Z. Benet

Abstract

This review summarizes the major advances that had been reported since the outstanding contributions that Professor Benet and his group had made in the 1980s and 1990s concerning the metabolism and pharmacologic action of organic nitrates (ORNs). Several pivotal studies have now enhanced our understanding of the metabolism and the bioactivation of ORNs, resulting in the identification of a host of cysteine-containing enzymes that can carry out this function. Three isoforms of aldehyde dehydrogenase, all of which with active catalytic cysteine sites, are now known to metabolize, somewhat selectively, various members of the ORN family. The existence of a long-proposed but unstable thionitrate intermediate from ORN metabolism has now been experimentally observed. ORN-induced thiol oxidation in multiple proteins, called the "thionitrate oxidation hypothesis," can be used not only to explain the phenomenon of nitrate tolerance, but also the various consequences of chronic nitrate therapy, namely, rebound vasoconstriction, and increased morbidity and mortality. Thus, a unifying biochemical hypothesis can account for the myriad of pharmacological events resulting from nitrate therapy. Optimization of the future uses of ORN in cardiology and other diseases could benefit from further elaboration of this unifying hypothesis.

Keywords: Enzymology; Metabolism; Nitric Oxide; Toxicology.

Fig. 1

The Thionitrate Oxidation Hypothesis of organic nitrate metabolism, bioactivation, and enzyme inactivation. PS = cysteine-containing proteins; SG = glutathione residue,-SO₂H = sulfinic acid protein modification and -SO₃H = sulfonic acid modification. Adapted from Fung

Fig. 2

Schematic showing how thiol oxidation in different proteins by organic nitrates (RONO₂) can lead to a wide array of pharmacological consequences. Adapted from Page and Fung