Nitric oxide is synthesized endogenously from l-arginine via the action of NO synthase (NOS). The isoforms of NOS have been further subdivided and now fall into three basic categories: (i) endothelial NOS (eNOS), (ii) neuronal NOS (nNOS), and (iii) inducible NOS (iNOS). Unlike eNOS and nNOS, iNOS is not expressed constitutively, but rather is expressed in most cell types given the appropriate stimulatory conditions.
Cells in the liver can be divided into the hepatic parench-ymal cells (hepatocytes) and the hepatic nonparenchymal cells, which are further subdivided into endothelial cells, smooth muscle cells, Kupffer cells, and hepatic stellate cells. Both hepatic parenchymal cells and hepatic nonparenchymal cells can express iNOS, whereas eNOS is constitutively expressed in hepatic endothelial cells. Although iNOS is not thought to be expressed constitutively in healthy liver, it is readily upregulated in the liver under a number of disease conditions, including ischemia-reperfusion injury, cirrhosis, hepatitis, and liver regeneration (1-4). The iNOS is also upre-gulated in vitro in hepatocytes and Kupper cells in response to endotoxin, proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1^ (IL-1^), and interferon^, as well as their combinations (5). These stimuli often act synergistically to induce iNOS expression; however, IL-1^ alone is an effective stimulator of iNOS in hepatocytes (6). The induction of iNOS gene by proinflammatory cytokines requires the activation of nuclear factor-KB (NF-kB) in human and rat hepatocytes (7). In addition, hepatic endothelial cells and stellate cells can also induce in vitro NO production through iNOS expression in response to proinflammatory cytokines (8). Therefore, in inflamed liver, hepatocytes are situated in an environment where NO is produced from surrounding cells, as well as themselves.
Nitric oxide is a highly labile molecule and, as such, is vulnerable to a lot of biological reaction once it is produced. NO, its oxidized form (NO+), and its reduced form (NO-) may all react with oxygen molecule and transition metals to form higher nitrogen oxides such as NO2~ or with various metals to form nitrosyl-metal complexes. Nitric oxide activates the hem center of soluble guanylate cyclase (sGC), which leads to intracellular increases in cyclic guanosine monophosphate (cGMP). Nitric oxide can interact with thiol groups, including glutathione and cysteine (9). Nitrosylation of biological thiols can influence protein functions in important ways. Nitric oxide can also interact with the superoxide anion. Interaction with NO neutralizes superoxide, thereby decreasing oxidative stress. However, this reaction can also lead to formation of peroxynitrite (ONOO) that can cause nitration of protein tyrosines (nitrotyrosine), contributing to enzymatic and cellular dysfunction (10).
Because NO production is significantly elevated in the liver under disease conditions, the physiological and patho-physiological functions of NO in the liver have been widely studied. Both cytoprotective and cytotoxic effects of NO have been demonstrated in the liver (Fig. 1).
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Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.