Nitrite: on the journey from toxin to therapy.
Nitrite: on the journey from toxin to therapy.
复制标题
亚硝酸盐：从毒素到治疗的旅程。
DOI：
10.1007/s40262-014-0231-5
复制
发表时间：
2015
影响因子：
4.5
通讯作者：
Power,GordonG
中科院分区：
文献类型：
--
作者：
Blood,ArlinB;Power,GordonG
Biomedical interest in the nitrite anion (NO2-) was once limited primarily to its toxic effects following ingestion of contaminated food or well water. The discovery that nitric oxide (NO) is an endogenously produced signaling molecule, and that nitrite is a relatively stable product of NO metabolism, brought increased focus on nitrite concentrations as an index of endogenous NO production. More recently, however, it has become apparent that nitrite is more than just a byproduct of NO, but that it can also be converted back into NO by a number of different biochemical pathways (see the recent review by Lundberg and Weitzberg [1]). As a result, nitrite is now widely regarded as a bioactive molecule with potentially wide-ranging physiological function and therapeutic application. A majority of circulating nitrite is derived from the oxidation of NO produced by endothelial NO synthase [2]. A significant portion of circulating nitrite is also derived from plasma nitrate (NO3-), which is concentrated* 10-fold from the plasma into the saliva where oral bacterial nitrate reductases efficiently reduce it to nitrite that is then swallowed and absorbed in the gastrointestinal tract [1]. Nitrite is metabolized in a number of different organs as well as in the blood, or excreted by the kidneys. When O2 is present, nitrite can be oxidized to produce nitrate. In contrast, under hypoxic conditions, nitrite can be reduced to NO that can then produce an array of nitrogen oxide species including nitrosothiols, N-nitrosamines, and ironnitrosyls. Nearly all of these products can be converted back into nitrite again under physiological conditions, raising the possibility of bidirectional flux between nitrite and these other nitrogen oxide species (Fig. 1). The recently described reduction of nitrate (NO3-) to nitrite (NO2-) in the mouth, and nitrite to NO in the tissues constitutes a nitrate? nitrite? NO axis that provides for NO production independent of the traditional NO synthase pathways. While the half-life of NO in whole blood (* 2 ms) is so short that the effects of free NO are limited to a few hundred microns from its site of production, the elimination half-lives of nitrite (15–30 min) and nitrate (4–6 h) are long enough for these species to serve as circulating reservoirs of NO bioactivity. Thus, the widely different biologic half-lives provide responses by NO in seconds, nitrite as a substrate for NO production changing over minutes, and nitrate as a large-capacity reservoir changing over hours.Most of the bioactivity of nitrite requires it first to be reduced to NO. This redox reaction can occur with a number of different proteins that carry transition metals such as hemoglobin, myoglobin, cytoglobin, and neuroglobin, other heme-containing proteins such as cytochrome c oxidase, and the molybdenum-containing proteins xanthine oxidase and aldehyde oxidase (see the recent review by Kim-Shapiro and Gladwin [3]). Importantly, when O2 binds to the transition metals of these proteins the reduction of nitrite to NO is blocked, and thus nitrite reduction to NO occurs only under hypoxic conditions when there is need for vasodilation and increased O2 delivery. This negative feedback system maintains O2 delivery without requiring neural or endocrine control. Nitrite can also be reduced to NO under acidic conditions in which it is protonated to form nitrous acid (HNO2, pKa= 3.2) that then decomposes into NO in seconds. As a result, significant amounts
