Nitric oxide and chemically induced hepatotoxicity: beneficial effects of the liver-selective nitric oxide donor, V-PYRRO/NO
Section snippets
Multiple and diverse effects of NO in the liver
Nitric oxide (NO), a paracrine-acting soluble gas enzymatically synthesized from l-arginine, is a unique biological molecule that has been implicated in a myriad of physiological and pathological processes. NO has a broad range of biological activities including the regulation of vascular tone, blood flow, neurotransmission, signal transduction, anti-microbial defense, immunomodulation, cellular redox status, and hepatocellular apoptosis. Once produced, NO has a short half-life and undergoes
The beneficial effects of NO donors in the liver
Based on the biological importance of NO, a variety of NO donor prodrugs have been developed. These NO prodrugs act either systemically or are targeted to specific organs including the liver. The more selective and organ-specific NO donors, including NONOates (Keefer, 2003), or other classes of NO donors (Janero, 2000) are being intensively studied for drug development. In the following section, the impacts of a few non-specific and liver-selective NO donors are discussed.
Sodium nitroprusside
The rationale of design and synthesis of V-PYRRO/NO
The desired strategy for designing NO donor prodrugs is to deliver NO to target cells or organs without affecting other organs. Efforts have been made to exploit the chemical versatility of diazeniumdiolates to achieve such tissue selectivity by anchoring the anionic diazeniumdiolates (NONOates) for targeted NO release to selective tissues (Keefer, 2003). Using this strategy, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a nitric oxide prodrug that targets the liver, was
Conclusion
The complex and diverse effects of NO in the liver are influenced by many physiological and pathological factors. The site and amount of NO production are critical. In general, increased endogenous NO production during acute hepatotoxicant insult can be envisioned as an adaptive response to acute inflammation and early sepsis, whereby NO serves to maximize the tissue perfusion, prevents platelet aggregation and thrombosis, and neutralizes reactive radical species. Inhibition of endogenous NO
Acknowledgements
The authors thank Drs. Elaine Leslie and Wei Qu for critical review during the preparation of this manuscript.
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