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Nitric oxide and chemically induced hepatotoxicity: beneficial effects of the liver-selective nitric oxide donor, V-PYRRO/NO Jie Liu∗ , Michael P. Waalkes Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709, USA Available online 21 December 2004

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. Published by Elsevier Ireland Ltd. Keywords: Nitric oxide; Hepatotoxicity; NO donor; V-PYRRO/NO; Hepatoprotection; iNOS; eNOS

1. Nitric oxide and the liver 1.1. Multiple and diverse effects of NO in the liver

∗ Corresponding author. Tel.: +1 919 541 3951; fax: +1 919 541 3970. E-mail address: [email protected] (J. Liu).

0300-483X/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.tox.2004.11.017

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

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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 halflife and undergoes spontaneous oxidation to the inactive metabolites nitrite and nitrate (Farzaneh-Far and Moore, 2001). The liver plays a central role in endogenous hormone metabolism, xenobiotic detoxication, and immune processes, and is a major organ influenced by NO under various liver disease conditions (Chen et al., 2003). NO often has complex and diverse roles in the liver. For example, NO may acts as both an inhibitor or as an agonist in hepatic cell signaling events (Laskin et al., 2001). Similarly, NO can have both pro- and antioxidant actions (Joshi et al., 1999; Fitzhugh and Keefer, 2000), and NO can both induce and inhibit apoptosis in the liver (Kim and Billiar, 2001). The factors dictating whether NO will have beneficial versus harmful effects in the liver include the amount and duration of NO exposure, the type of non-NO related toxic insults, and the pathological status of the liver. This chapter reviews endogenous NO production in the liver in response to various hepatotoxicants, the beneficial and harmful effects of NO synthesis inhibition, the eNOS and iNOS knockout animal models, and the beneficial effects of NO donor prodrugs on chemically induced liver toxicity. The liver-selective NO donor, V-PYRRO/NO, will be used as an example in this review, to demonstrate the diverse impact that NO can have on the liver.

a consistent finding associated with early hepatotoxicity. Increased NO production has been proposed to play a role as a proinflammatory mediator to kill damaged hepatocytes in the case of acetaminophen overdose (Gardner et al., 1998) or endotoxemia (Laskin et al., 1995). However, increased NO can also function as an adaptive response to acute hepatic inflammation and early sepsis, since NO serves to maximize tissue perfusion, prevents platelet aggregation and thrombosis, and neutralizes reactive radical species (Farzaneh-Far and Moore, 2001; Farghali et al., 2002; Chen et al., 2003). In addition, NO also has anti-microbial properties, prevents neutrophil activation, and acts as a signal for biosynthesis of hepatoprotective proteins. An appropriate amount of NO production can also have antiapoptotic effects in hepatocytes (Chen et al., 2003). Therefore, NO overproduction may play a role in cell population restructuring (apoptosis) after toxic insult to the liver (Gardner et al., 1998), while in other instances it acts to reduce apoptosis potentially through maximization of liver perfusion. Thus, increased NO production in response to hepatotoxicants is a common phenomenon, which could be beneficial or harmful depending on the amount and duration of NO production as well as the type of toxic insult and the pathological status of the liver.

1.2. Increased NO production in response to hepatotoxicants

The production of endogenous NO is through the enzyme NO synthetase (NOS) that occurs in several forms including iNOS, which is common throughout tissues, and eNOS which occurs primarily in endothelial cells (Farzaneh-Far and Moore, 2001; Chen et al., 2003). Because of the association of increased NO production with various liver diseases, efforts have been made to reduce endogenous NO production using various NO synthetase inhibitors. Inhibition of endogenous iNOS is beneficial in certain conditions such as endotoxemia and ischemia–reperfusion induced liver injury (Laskin et al., 1995; Hierholzer et al., 1998). However, blocking NO production is not always beneficial, and contradictory results have been reported. For example, in one study inhibition of NO production by the specific iNOS inhibitor aminoguanidine was observed to protect against acetaminophen hep-

The body’s defense system can synthesize a variety of proteins in response to toxic stimuli, such as metallothionein, heme oxygenase-1 and heat-shock proteins. Increased NO production has also been reported in response to various pathological conditions and toxic insults. For example, NO production in the liver is increased during endotoxemia (Laskin et al., 1995) and ischemic reperfusion (Hierholzer et al., 1998). Overproduction of NO is also observed with hepatotoxicity induced by acetaminophen (Hinson et al., 1998), ethanol (Spitzer et al., 2002), carbon tetrachloride (Weber et al., 2003), concanavalin A (Sass et al., 2002), cadmium (Harstad and Klaassen, 2002), and numerous other agents. Thus, NO overproduction is

1.3. Inhibition of endogenous NO production has beneficial and adverse effects in the liver

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atotoxicity in mice (Gardner et al., 1998). In contrast, the same compound used in another mouse study enhanced acetaminophen toxicity (Hinson et al., 2002). Inhibition of iNOS production by NG -nitro-l-arginine methyl ester (l-NAME) protected against endotoxininduced liver injury in one study (Laskin et al., 1995), while in another study was found to increase the toxicity of endotoxemia (Bohlinger et al., 1995; Wang et al., 1995). The highly selective and potent iNOS inhibitor l-N6 -(1-imino-ethyl)lysine (l-NIL) did not attenuate liver damage caused by endotoxin despite the fact that it prevented endotoxin-induced circulation failure (Wray et al., 1998). l-NIL has also been shown to exacerbate hepatic apoptosis in liver grafts (Yagnik et al., 2002). Thus, inhibition of endogenous iNOS is not always of benefit during hepatotoxicity. iNOS inhibitors have been shown to have no effect on hepatotoxicity induced by cadmium (Harstad and Klaassen, 2002) or acetaminophen (Hinson et al., 2002). In addition, inhibition of iNOS can even weaken the body’s defensive mechanisms against hepatotoxic stimuli as in the case with carbon tetrachloride (Tanaka et al., 1999). Thus, inhibitors of NO synthetase have both positive and negative effects with regard to hepatotoxicity, and their biological effects are dependent on pathological conditions.

sistent. In ischemia–reperfusion-induced liver injury, iNOS−/− mice showed increased (Hines et al., 2002), decreased (Lee et al., 2001), or unaltered toxicity (Kawachi et al., 2000). In endotoxin-induced liver injury, iNOS−/− mice showed increased (Hickey et al., 1997) or decreased (Koerber et al., 2002) liver injury. In acetaminophen-induced hepatotoxicity, iNOS−/− mice showed decreased toxicity in some instances (Gardner et al., 2002), while other studies showed no effect (Michael et al., 2001). In addition, the sensitivity of iNOS−/− mice to hepatoxicants varies depending on physio-pathological conditions of the liver. For example, iNOS−/− mice showed increased sensitivity to carbon tetrachloride (Morio et al., 2001), decreased susceptibility to Jo2 (a Fas ligand antibody)mediated hepatotoxicity (Chang et al., 2003), or unaltered sensitivity to cadmium hepatotoxicity (Harstad and Klaassen, 2002). iNOS−/− mice also exhibited down-regulation of hepatic cytochrome P450 enzymes (Sewer et al., 1998) and impaired liver regeneration (Rai et al., 1998). Thus, the selective disruption of the iNOS gene can have variable responses to hepatotoxicants, depending on experimental conditions.

1.4. iNOS null mouse models

2.1. The beneficial effects of NO donors in the liver

Studies with transgenic animals with specific gene knockout have greatly advanced our understanding of the biological functions of many genes and/or proteins. The use of eNOS null (−/−) and iNOS null (−/−) mice has been critical for elucidation of the role of NO in hepatotoxicity. Selective disruption of the eNOS gene has been shown to be harmful, as endothelial-derived NO is important in maintaining liver microcirculation and vascular tone (Rockey, 2003). eNOS−/− mice exhibit enhanced liver injury in ischemia–reperfusion models (Hines et al., 2002; Lee et al., 2001; Kawachi et al., 2000). Similarly, eNOS−/− mice are also sensitive to portal vein ligation induced portal hypertension (Theodorakis et al., 2003). iNOS is the major NO synthetase inducible in response to various hepatotoxicants and/or stimuli. However, the results concerning chemically induced liver injury from iNOS−/− mice are also not con-

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 nonspecific and liver-selective NO donors are discussed. Sodium nitroprusside (SNP) at pharmacological doses is reported to protect against TNF␣-induced liver toxicity (Bohlinger et al., 1995), possibly by attenuating the detrimental effects of TNF-␣ on liver microcirculation (Gundersen et al., 1998) and thus reducing inflammatory responses and cytokine gene expression (Anaya-Prado et al., 2003). In addition, SNP is also an effective protector against interferon gamma/LPS toxicity, possibly by suppression of caspase-3 (So et al., 2001). However, SNP is not specific for NO donation to

2. NO donors and the liver

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the liver and the systemic effects of SNP are prohibitive for general use against hepatotoxic insult. The novel spontaneous NO donor FK409, has been shown to be effective in protecting against ischemia–reperfusion-induced liver injury in rats (Ohmori et al., 1998) and dogs (Shimamura et al., 1999; Aiba et al., 2001). FK409 treatment improves hepatic microcirculation in ischemia–reperfusion models, decreases liver enzyme release, and increases the survival rate of ischemic animals. However, FK409 is non-specific and systemic hypotension was observed in dogs treated with the compound (Shimamura et al., 1999). Thus, a liver-selective NO donor would be a desired therapeutic tool. Molsidomine, a compound metabolized by the liver into 3-morpholinosydonimine which releases NO and superoxide simultaneously on oxidation by O2 (Rosenkranz et al., 1996), is relatively liver-selective. Molsidomine is effective in protecting against the liver injury produced by endotoxin (Kumins et al., 1997) and bile-duct ligation (Ozturk et al., 2002). Inflammatory cell infiltration and cytokine production are reduced by molsidomine administration. In bile-duct ligated rats challenged with endotoxin, molsidomine increased animal survival rates, attenuated caspase-3 activation and reduced liver enzyme release (Brown et al., 2003). NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively releases NO within the liver (Fiorucci et al., 2001a), and has been shown to protect animals from liver injury produced by concanavalin A (an autoimmune hepatitis model), Jo2 (a Fas-mediated apoptosis model), ␣-naphthylisothiocyanate (an intrahepatic cholestasis model), or chronic carbon tetrachloride (a cirrhosis model) (Fiorucci et al., 2001a, 2001b, 2002a, 2003; Loureiro-Silva et al., 2003). The beneficial effects of NCX-1000 are attributed to an ability to maintain hepatic microcirculation, prevent portal hypertension (Fiorucci et al., 2001a, 2003; Loureiro-Silva et al., 2003), inhibit inflammatory responses, and suppress caspase-3 mediated apoptosis (Fiorucci et al., 2001b, 2002a). In addition, Spermine NONOate has been shown to protect against ischemia–reperfusion-induced liver injury in rats (Peralta et al., 2001), and to inhibit bile acidinduced apoptosis through inhibition of caspase-3 activity in isolated hepatocytes (Gumpricht et al., 2002). The majority of the reported studies indicate that NO

donors have beneficial effects; however, the negative effects of the NO donors may not be reported. Nevertheless, the use of the liver-selective NO donors seems to be beneficial in various liver disorders. 2.2. NO-releasing acetaminophen NO-releasing non-steroid anti-inflammatory drugs (NO-NSAIDs) are reported to diminish some of the NSAIDs’ side effects and are safer than the parent compounds (Janero, 2000). Similarly, the NO-releasing derivative of acetaminophen (nitroacetaminophen, NCX-701) also shows beneficial effects. It is well known that an overdose of acetaminophen produces liver injury. However, when a normally hepatotoxic dose of acetaminophen is given as nitroacetaminophen, hepatotoxicity is not observed while there is no reduction in anti-inflammatory and anti-nociceptive effects (Futter et al., 2001). Nitroacetaminophen is as effective as acetaminophen in controlling endotoxin-induced fever, shares the same metabolic profiles (glucuronidation and glutathione conjugation) as acetaminophen, but does not produce liver injury in mice as compared to acetaminophen when hepatotoxic doses are given. Nitroacetaminophen appears to act through NO inhibition of Fas-mediated cell death pathways and at several checkpoints in the acetaminophen-induced apoptosis (Fiorucci et al., 2002b). Based on mitigation of hepatotoxic potential, nitroacetaminophen could be an attractive alternative to acetaminophen and is currently in clinical trials (Moore and Marshall, 2003).

3. The liver-selective NO donor, V-PYRRO/NO 3.1. 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)diazen1-ium-1,2-diolate (V-PYRRO/NO), a nitric oxide prodrug that targets the liver, was created by adding a

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Fig. 2. Effect of V-PYRRO/NO on acute hepatotoxicity produced by d-galactosamine/endotoxin (GlaN/LPS, 700 mg/10 ␮g/kg), acetaminophen (APAP, 200 mg/kg), cadmium (Cd, 3.7 mg/kg), and alpha-naphthylisothiocyanate (ANIT, 150 mg/kg) in mice. Liver injury was evaluated by serum alanine aminotransferase (ALT) activity. Data are expressed as relative fold-increase over controls with mean ± S.E.M. of 6–20 mice. * Significantly different from toxicant alone, P < 0.05 (adapted from Liu et al., 2002, 2003, 2004).

Fig. 1. The structure and the mode of NO release from VPYRRO/NO.

vinyl functional group to the terminal oxygen of pyrrolidine diazeniumdiolate (Fig. 1, Saavedra et al., 1997). V-PYRRO/NO is a stable diazeniumdiolate which circulates freely throughout the body until it is enzymatically converted to NO in the liver likely by cytochrome P450s (Saavedra et al., 1997; Stinson et al., 2002). The release of NO from V-PYRRO/NO into hepatocytes has been confirmed by the detection of increased nitrite/nitrate levels, and by the stimulation of hepatic cyclic guanosine 3 ,5 -monophosphate (cGMP) production (Saavedra et al., 1997; Ou et al., 1997). In addition, pharmacokinetic studies show a high first-pass effect through the liver, with a blood half-life of approximately 12 min (Stinson et al., 2002). Once activated, the local NO half-life released from V-PYRRO/NO is very short (Saavedra et al., 1997). 3.2. The effect of V-PYRRO/NO on hepatic vasculature V-PYRRO/NO has beneficial effects by increasing liver blood flow to maintain hepatic microcir-

culation. This has been shown in animal models of ischemia–reperfusion (Ricciardi et al., 2001) and bileduct-ligation-induced portal hypertension (Moal et al., 2002). V-PYRRO/NO improves hepatic microcirculation and preserves sinusoid endothelial cell integrity in moncrotaline-induced hepatic sinusoid obstruction syndrome (Deleve et al., 2003). Thus, V-PYRRO/NO seems to preserve hepatic microcirculation, which could be an important aspect of its hepatoprotective effects (discussed below). 3.3. The protective effects of V-PYRRO/NO against acute hepatotoxicity Beneficial effects of V-PYRRO/NO in chemically induced acute hepatotoxicity in intact animals are summarized in Fig. 2. V-PYRRO/NO is very effective in decreasing the hepatotoxicity of dgalactosamine/endotoxin (Liu et al., 2002), supporting earlier findings about the protective effects of VPYRRO/NO on the hepatotoxicity produced by dgalactosamine/TNF-␣ in rats (Saavedra et al., 1997), and in cultured hepatocytes (Ou et al., 1997; Kim et al., 2000). V-PYRRO/NO also protects against acetaminophen hepatotoxicity in mice (Liu et al., 2003),

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and this protection is both dose- and time-dependent. The protection of V-PYRRO/NO does not seem to be due to altered toxicant metabolism, as it is still effective even when given simultaneously or 90 min after the administration of GlaN/LPS or acetaminophen (Liu et al., 2002, 2003). Whether V-PYRRO/NO can afford protection against inorganic hepatotoxicants was examined using cadmium as a model. Multiple V-PYRRO/NO injections protect against Cd hepatotoxicity, and this protection is not mediated by any alteration of Cd distribution to the liver or by an induction of metallothionein. The suppression of cadmium-induced inflammation appears key to the inhibitory effect of V-PYRRO/NO on cadmium hepatotoxicity. V-PYRRO/NO thus inhibits the progress of cadmium-induced endothelial cell injury to parenchyma cell death (Liu et al., 2004). Another hepatotoxicant we tested was alphanaphthylisothiocyanate (ANIT). In the case of ANIT, V-PYRRO/NO afforded only partial protection without affecting ANIT-induced cholestasis (Liu et al., unpublished observation). In both cases, neutrophil-mediated inflammation was greatly suppressed by the NO donor. With regard to impact on the hepatotoxicity produced by phalloidin (a microtubule hepatotoxicant) and Jo2 (a Fas-ligand mediated hepatotoxicant), VPYRRO/NO was ineffective (data not shown). Thus, the beneficial effects of V-PYRRO/NO depend on the type of toxic insults. V-PYRRO/NO provides the best protection against endotoxin/TNF-␣ and acetaminophen-induced hepatotoxicity, moderate protection against cadmium and ANIT, and has no impact on several other hepatotoxicants. 3.4. The possible mechanism of beneficial effects of V-PYRRO/NO Like all the NO donors, the primary target of VPYRRO/NO is most likely the endothelium (Rockey, 2003), where free NO acts to preserve liver microcirculation. Evidence for this includes V-PYRRO/NOinduced reduction in hypertension (Moal et al., 2002), as well as protection against ischemia–reperfusion injury (Ricciardi et al., 2001) and sinusoid occlusion (DeLeve et al., 2003). In V-PYRRO/NO-induced protection against various hepatotoxicants, reduced hepatic congestion and improved liver microcirculation are the most notable findings, and could be a primary mech-

anism of hepatoprotection. As a result of preserving the vasculature, inflammatory responses are suppressed, as reflected by reduced expression of genes encoding for neutrophil chemotaxis, and neutrophil and/or macrophage activation that results in the release of proinflammatory cytokines (e.g., IL-1, IL-6 and TNF-␣). The anti-inflammatory effects of V-PYRRO/NO are evident in various chemically induced hepatotoxicity models. This could be a general mechanism for the beneficial effects of NO donors in liver pathologies. The anti-apoptotic effects of V-PYRRO/NO are important mechanisms in hepatoprotection. V-PYRRO/NO administration can suppress endotoxin/TNF-␣-induced liver cell apoptosis in vivo (Saavedra et al., 1997; Liu et al., 2002, 2003), and in vitro (Ou et al., 1997; Kim et al., 2000). V-PYRRO/NO when given alone can also suppress the expression of TNF-␣ and apoptosis-related genes such as caspase-3 (Liu et al., 2002). In addition, V-PYRRO/NO can inhibit caspase-3 activity by S-nitrosylation (Kim et al., 2000). Thus, the anti-apoptotic properties, either as a direct or indirect effect from improved hepatic microcirculation, contribute to the protective effects of V-PYRRO/NO against hepatotoxicants. Induction of protective proteins could be another mechanism. V-PYRRO/NO has been shown to increase HSP 70 (Kim et al., 1997), which could play a role in V-PYRRO/NO-mediated hepatoprotection. In addition, NO is an important mediator for heme oxygenase (HO-1) induction (Zamora et al., 2002), and an inhibitor for transcription factors such as the AP-1 transcription complex (Buzard and Kasprzak, 2000). Overall, multiple mechanisms have been proposed for V-PYRRO/NO and/or NO in hepatoprotection. These mechanisms are not mutually exclusive and could play an integrated role in executing the beneficial effects of NO in the liver.

4. 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 per-

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fusion, prevents platelet aggregation and thrombosis, and neutralizes reactive radical species. Inhibition of endogenous NO synthesis is only hepatoprotective under certain circumstances, and in some cases of no benefit. Similarly, transgenic mice null for iNOS show that disruption of endogenous NO production has beneficial effects only with certain types of toxic insults, but in general results in a compromise of the body’s defense mechanisms. The dose differentiates a remedy from a poison and is likely responsible for the dual protective or detrimental effects of NO in the liver. Selective delivery via organ-specific NO donor prodrugs is now in development, and could provide fundamental information for the development of beneficial NO donors for liver diseases.

Acknowledgements The authors thank Drs. Elaine Leslie and Wei Qu for critical review during the preparation of this manuscript.

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