Nitric oxide and chemically induced hepatotoxicity: beneficial effects of the liver-selective nitric oxide donor, V-PYRRO/NO

doi:10.1016/j.tox.2004.11.017

Toxicology

Volume 208, Issue 2, 15 March 2005, Pages 289-297

https://doi.org/10.1016/j.tox.2004.11.017 Get rights and content

Abstract

Nitric oxide (NO) is endogenously produced by the enzyme NO synthase in the cell or pharmacologically delivered to tissues as NO prodrugs. This simple molecule is a potent biological mediator in a myriad of physiological and pathological events. The liver plays a central role in metabolism and immune processes, and is a major target organ influenced by NO. NO production in the liver is usually increased in response to acute insult with hepatotoxicants, and may be decreased during chronic liver diseases. The induction of NO production could be envisioned as an early adaptive response, which may become a mediator of tissue damage when in excess. In this regard, inhibition of endogenous NO synthase has been shown to be beneficial in some cases and detrimental in others. The creation of eNOS and iNOS knockout animals has advanced our understanding of NO function in hepatic response to toxic insults. Knocking endogenous NO production can be beneficial in response to certain toxicants; however, in general it weakens the body's defense mechanisms against toxic insults. A variety of pharmacological NO prodrugs have been developed, and, when used appropriately, most of them have demonstrated beneficial effects in the liver in a variety of pathological settings. In this review, we discuss the relationship between NO and hepatotoxicity, and the beneficial effects of NO donors on the liver, using the liver-selective NO donor, V-PYRRO/NO, as an example to demonstrate that pharmacologically delivered NO could have therapeutic benefits for liver disorders.

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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Published by Elsevier Ireland Ltd.

Nitric oxide and chemically induced hepatotoxicity: beneficial effects of the liver-selective nitric oxide donor, V-PYRRO/NO

Abstract

Section snippets

Multiple and diverse effects of NO in the liver

The beneficial effects of NO donors in the liver

The rationale of design and synthesis of V-PYRRO/NO

Conclusion

Acknowledgements

J. Am. Coll. Surg.

Toxicol. Lett.

J. Am. Coll. Surg.

Arch. Biochem. Biophys.

Hepatology

Int. Immunopharmacol.

Digest. Liver Dis.

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J. Biol. Chem.

Toxicology

Nitric Oxide

Free Radic. Biol. Med.

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Hepatology

Hepatology

Hepatology

Hepatology

Hepatology

Nitric Oxide

Hepatology

Digest. Liver Dis.

Toxicol. Appl. Pharmacol.

Nitric Oxide

Hepatology

J. Am. Coll. Surg.

Gastroenterology

Gastroenterology

Hepatology

Nitric Oxide

The attenuation of hemorrhage-induced liver injury by exogenous nitric oxide, l-arginine, and inhibition of inducible nitric oxide synthase

J. Invest. Surg.

Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: a review

J. Environ. Pathol. Toxicol. Oncol.