Nitric oxide and chemically induced hepatotoxicity: beneficial effects of the liver-selective nitric oxide donor, V-PYRRO/NO.
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.
Liu
Jie
J
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709, USA. liu6@niehs.nih.gov
Waalkes
Michael P
MP
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D015262:Xenobiotics / Q000009:adverse effects*
D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D015262:Xenobiotics; D009569:Nitric Oxide