Discussing Endogenous NO^•/HNO Interconversion Aided by Phenolic Drugs and Vitamins

Abstract

The reduction of NO(•) to HNO/NO(-) under biologically compatible conditions has always been thought as unlikely, mostly because of the negative reduction potential: E°(NO(•),H(+)/HNO) = -0.55 V vs NHE at physiological pH. Nonetheless, during the past decade, several works hinted at the possible NO-to-HNO conversion mediated by moderate biological reductants. Very recently, we have shown that the reaction of NO(•) with ascorbate and aromatic alcohols occurs through a proton-coupled nucleophilic attack (PCNA) of the alcohol to NO(•), yielding an intermediate RO-N(H)O(•) species, which further decomposes to release HNO. For the present work, we decided to inspect whether other common biological aromatic alcohols obtained from foods, such as Vitamin E, or used as over-the-counter drugs, like aspirin, are able to undergo the reaction. The positive results suggest that the conversion of NO to HNO could occur far more commonly than previously expected. Taking these as the starting point, we set to review our and other groups' previous reports on the possible NO-to-HNO conversion mediated by biological compounds including phenolic drugs and vitamins, as well as several thiol-bearing compounds. Analysis of revised data prompted us to ask ourselves the following key questions: What are the most likely physio/pathological conditions for NO(•)-to-HNO conversion to take place? Which effects usually attributed to NO(•) are indeed mediated by HNO? These inquiries are discussed in the context of 2 decades of NO and HNO research.

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

“…130 Extended work shows the ability of other biologically relevant phenols including vitamin E (tocopherol) and the drugs acetaminophen and salicylic acid facilitate the conversion of NO to HNO. 154 Overall, these results provide a unique potential endogenous pathway for the conversion of NO to HNO in the presence of these “reducing” alcohols and theoretically make any NO source a source of HNO. Given the numerous systems capable of reducing nitrite (NO 2 − ) to NO and the known conversion of dietary nitrate to nitrite by oral bacteria in humans and the subsequent chemical or enzymatic reduction of nitrite to NO, a large number of potential endogenous HNO generating systems appear possible.…”

Reduction Potential of RuIII-Based Complexes with Potential Antitumor Activity and Thermodynamics of their Hydrolysis Reactions and Interactions with Possible Biological Targets: a Theoretical Investigation

“…However, in the biological medium, it is not straightforward to attribute a preferred pathway for the mechanism of action, since several processes can alter the reduction potential of the drug and, therefore, alter the rate of the solvolysis process. For instance, in the biological medium the prodrugs can be reduced by well-known biological reductants such as reduced nicotinamide adenine dinucleotide (NADH), ascorbate, tocopherol (vitamin E), Cys and GSH, for which the reduction potential at physiological pH is around -0.3 to -0.5 V. 63,64 However, the reaction mechanism involved in the reduction of these complexes is not known and, therefore, in the time scale required for the biological reduction of these prodrugs, solvolysis can takes place. NMR experiments have shown that, under buffered conditions, KP1019 is reduced within 3.5 h in the presence of GSH and within min in the presence of ascorbic acid.…”

The chemical biology of HNO signaling

“…In spite of the apparent difficulty in NO reduction via abstraction of a hydrogen atom (radical) or electron transfer, several recent reports indicate that NO is capable of being reduced by alcohols (especially phenols or “activated” –OH groups) to give HNO [34, 35]. Since the O-H BDEs for HO-H and phenyl-O-H are 119 and 88 kcal/mole, respectively, it remains to be determined how this chemistry occurs.…”

“…Also, Janzen et al [38] have reported the reaction of phenolic antioxidants with an excess of NO (also under non-physiological conditions), yielding products characteristic of reversible O-nitroso formation, and EPR signals consistent with phenoxyl radicals were observed upon removal of NO from the solution. As mentioned above, the idea of NO reduction by alcohols has been recently revisited [34,35], and the proposal of a proton-coupled nucleophilic attack of phenolic or ascorbate oxygen upon the nitrogen of NO with concurrent or concomitant proton transfer has been put forth. It is proposed that ensuing O-N cleavage yields the resultant phenoxyl radical and HNO.…”