isoprostanes and the liver

Chemistry and Physics of Lipids 128 (2004) 125–133

Review

Isoprostanes and the liver

Kevin Moore∗

Centre for Hepatology, Royal Free and University College Medical School, University College London, London, UK

Abstract

The liver has been central to our understanding of the physiology and biology of the F2-isoprostanes. The discovery of F2-IsoPsand the initial demonstration that they could be used to localize oxidative stress was first demonstrated in a rat model of oxidativeliver injury (carbon tetrachloride), and the first demonstration that plasma concentrations are increased in a human disease wasin patients with liver failure and the hepatorenal syndrome [J. Clin. Invest. 90 (6) (1992b) 2502; J. Lipid Mediat. 6 (1/3) (1993)417]. This article will cover the measurement of F2-IsoPs as markers of lipid peroxidation in vivo in liver disease, and reviewtheir biological activity as mediators of disease.© 2003 Elsevier Ireland Ltd. All rights reserved.

Keywords: Isoprostanes; Hepatorenal syndrome; Liver; Oxidative stress

1. F2-Isoprostanes as markers of oxidative stressin liver disease

As is evident from other articles in this series, themeasurement of F2-IsoPs is now considered to be thegold standard for the assessment of oxidative injury invivo (Moore and Roberts, 1998).

1.1. What body fluids or tissue shouldbe sampled?

One of the most useful aspects of using the mea-surement of F2-IsoPs to assess oxidative stress is thefact that F2-IsoPs are present in all biological tissues orfluids studied. Thus, with respect to the liver F2-IsoPscan be measured in plasma, liver tissue, bile, orurine.

∗ Tel.: +44-207-433-2876; fax:+44-207-433-2877.E-mail address: [email protected] (K. Moore).

1.2. Plasma F2-IsoPs

Over 90% of F2-IsoPs present in plasma are carriedas lipid-esters (presumably in the LDL/HDL parti-cles), with the remainder circulating as free F2-IsoPs.Low concentrations of free F2-IsoPs are present inhuman plasma (∼20 pg/ml) (Morrow et al., 1995;Ikizler et al., 2002). However, much higher levelsof F2-IsoPs are present in plasma esterified to lipids(Ferraro et al., 2003). Following base-hydrolysis ofplasma lipids, the concentration of free F2-IsoPs in-creases from 20 to∼250 pg/ml (Ferraro et al., 2003).Thus, the majority of F2-IsoPs are esterified to plasmalipids. Free F2-IsoPs are formed by oxidation of tis-sue or plasma lipids, and then released as the freeacid by the action of a phospholipase. The half lifeof F2-IsoPs is short, being less than 20 min in the rat.Measurement of free F2-IsoPs in plasma provides anindex of total body production of F2-IsoPs, represent-ing the equilibrium between the formation as ester-ified F2-IsoPs, release as the free acid, metabolism

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126 K. Moore / Chemistry and Physics of Lipids 128 (2004) 125–133

and excretion. One potential problem with analysisof IsoPs in plasma is that the drawing of blood isreported to cause the generation of F2-IsoPs duringplatelet activation through a cyclo-oxygenase depen-dent pathway, or through monocyte activation, unlessspecial precautions are used (Pratico et al., 1995).This has led FitzGerald’s group to propose measure-ment of IPF2�-I, a class I isomer of the F2-IsoPsunder the alternative classification that they have pro-posed (Pratico et al., 1998a). However, the extent towhether this is a major methodological problem isstill under some dispute. Administration of NSAIDShas little or no effect on the urinary excretion ofF2-IsoPs in man or rats, suggesting that endogenousplatelet activation does not contribute much, if at all,to the urinary levels of F2-IsoPs.

When assessing systemic oxidative stress in vivo,it is not yet clear whether it is better to measure freelevels or esterified concentrations of F2-IsoPs. Mypersonal view is that is likely to be best to measurethe concentrations of free F2-IsoPs, as these seem tochange more dynamically during disease processes. Itmaybe that plasma esterified levels mainly representthe interaction of blood at the endothelial interface,whereas free levels represent the balance as describedabove.

1.3. Urinary F2-IsoPs

Measurement of urinary F2-IsoPs provides atime-integrated index of systemic F2-IsoP formation,since plasma (levels of∼20 pg/ml) are filtered at thekidney at the glomerular filtration rate (∼100 ml/min,equivalent to 2 ng/min), and F2-IsoPs are concen-trated and excreted. However, analysis of urine forun-metabolized F2-IsoPs has some limitations. It islikely that there is some contribution to urinary levelsfrom local formation of IsoPs in the kidney, which areexcreted directly into the urine (Morrow et al., 1993,1999; Moore et al., 1998). The potential limitations ofusing levels of un-metabolized F2-IsoPs in the urinecan be overcome by measurement of the urinary ex-cretion of a metabolite of F2-IsoPs. This is because (a)metabolism of prostaglandins occurs predominantlyin extra-renal tissues, (b) urine collected over severalhours can provide an integrated index of F2-IsoP pro-duction over time, (c) collection of urine for analysisis non-invasive, and (d) F2-IsoP metabolites cannot

be generated artifactually ex vivo by auto-oxidation.Toward this goal, the identification of the major uri-nary metabolite of the F2-IsoP, 15-F2t-IsoP, in humansas 2,3-dinor-5,6-dihydro-15-F2t-IsoP was recentlyreported (Roberts et al., 1996), and subsequently ahighly accurate stable isotope dilution GC/NICI/MSassay for this metabolite has been developed (Morrowet al., 1999). The measurement of the urinary excre-tion of this metabolite will prove to be an importantadvance in assessing oxidative stress status in vivoin humans that will be applicable to large clinicalstudies (Burke et al., 2000).

1.4. Hepatic F2-IsoPs

The levels of F2-IsoPs in normal liver are∼1–10 ng/g of wet tissue depending on species(Fernando et al., 1998; Harry et al., 1999). Thus, inthe first study on F2-IsoPs it was shown that admin-istration of carbon tetrachloride to rats increased bothhepatic and renal levels of esterified F2-IsoPs, andlocalized oxidative injury to these tissues (Morrowet al., 1992b; Awad et al., 1994a,b). Moreover, admin-istration of enzyme inducing agents to enhance themetabolism of carbon tetrachloride to its toxic radical,or administration of a glutathione depleting drug in-creased the formation of F2-IsoPs in liver tissue. Thiswas followed by a sustained release of F2-IsoPs fromliver, and an increase in plasma concentrations (Fig. 1).

There is, however, one caveat that is often ignored.F2-IsoPs are initially formed as esters in tissue lipidsand then released. In certain disease processes theremay be very marked up-regulation of phospholipases,so that tissue levels do not increase. This may be anadaptive response to prevent or circumvent the ac-cumulation of oxidized lipids in the cell membranewith secondary disruption of membrane function andfluidity (Morrow et al., 1992a). Thus, it is not sur-prising that the rate of hydrolysis of F2-IsoPs fromtissue lipids may exceed the rate of formation. Thus,the timing of sample collection may be critical. Forexample Harry et al. studied the effect of lipopolysac-charide (LPS) in control and bile duct ligated (BDL)cirrhotic rats. Initially the levels of hepatic esterifiedF2-IsoPs were measured at 3 h, but F2-IsoPs remainedunchanged. It was only when levels of F2-IsoPswere measured 1 h post LPS injection, that a sig-nificant increase in liver and kidney esterified levels

K. Moore / Chemistry and Physics of Lipids 128 (2004) 125–133 127

Levels of F2-isoprostanes esterified in plasma lipids of rats at various times

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Fig. 1. Administration of carbon tetrachloride to rats results in a rapid increase in hepatic esterified F2-IsoPs, which are then subsequentlyreleased, with an increase in plasma concentrations. Adapted from Morrow et al., 1992b.

of F2-IsoPs could be observed in cirrhotic rats com-pared to controls (Harry et al., 1999). The esterifiedF2-IsoPs peaked at 1 h before falling to basal levelsin both groups. Injection of endotoxin (LPS) caused a

Endotoxin causes a transient elevationof hepatic isoprostanes

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Fig. 2. Rats were injected with LPS at 0.5 mg/kg att = 0. Therewas a marked increase in the level of esterified F2-IsoPs in liveror kidney in cirrhotic rats at 1 h compared with controls. Con-trol animals also exhibited a significant increase in the levels ofisoprostanes in the tissue at 1 h. The most striking observationwas, however, the normalization of tissue levels within 3 h of LPSinjection.

much greater increase in plasma F2-IsoPs in the cir-rhotic rats compared with controls, however the levelspeaked at three hours, consistent with formation intissue and release (Harry et al., 1999; Fig. 2)

These results could be explained by the activationof a phospholipase by endotoxin in vivo. It has previ-ously been shown that Kupffer cell phospholipase A2activity increases four-fold within 2 h of injection ofendotoxin, and continues to rise thereafter. Thus, fol-lowing the injection of LPS (endotoxin) there is rapidformation, and rapid removal of F2-IsoPs from theliver and kidney of normal and cirrhotic rats.

2. Isoprostanes and oxidative stress in liver disease

2.1. Human studies

2.1.1. Hepatorenal syndromeThe pathophysiology of hepatorenal syndrome

(HRS) is not yet fully established. Studies have shownmarkedly reduced renal blood flow in patients withHRS (for review, seeMoore, 1997). In collabora-tion with Roberts and Morrow, we were the first todemonstrate increased plasma F2-Isoprostanes in pa-tients with the hepatorenal syndrome. The rationalefor this study was the known renal vasoconstrictingeffects of 8-iso-PGF2�. As shown inFig. 3, plasma


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Fig. 3. Plasma F2-IsoPs were measured by GCMS. There wasa marked elevation in the plasma concentrations in patients withhepatorenal syndrome (HRS), compared with those with ascitesbut normal renal function, or those with compensated liver disease(CLD).

concentrations were markedly elevated in patientswith HRS. Moreover, infusion of superoxide dismu-tase resulted in a 50% decrease of plasma F2-IsoPs inthree patients studied (data not shown) within 30 minof infusion.

The question of cause and effect of F2-IsoPs in HRSremains. F2-IsoPs have been shown to be cause vaso-constriction in the renal vasculature (Morrow et al.,1990). In addition, some F2-IsoPs may meditate theiractions via endothelin-1 (ET-1). (Yura et al. (1999)demonstrated that 8-iso-PGF2� can stimulate cell pro-liferation, DNA synthesis and ET-1 mRNA expressionin bovine aortic endothelial cells at physiological con-centrations. The proliferative effect was partially abol-ished by treatment with anti-endothelin antibody. Thismay be directly relevant to patients with HRS, sinceboth plasma concentrations of F2-IsoPs and ET-1 aresignificantly increased (Moore et al., 1992; Morrowet al., 1993), although there are no data on whether cir-culating levels of F2-IsoPs induce an increase in ET-1synthesis.

2.2. Alcoholic liver disease

It was believed for a long time that alcohol causesfree radical induced liver injury. However, it was notuntil Meagher et al. (1999)demonstrated that acutealcohol administration to normal subjects increasesurinary F2-IsoPs, that this was finally resolved. In thisstudy, they administered alcohol acutely to ten healthyvolunteers, and observed a dose-dependent increase

in urinary F2-IsoP excretion with respect to alco-hol. In a separate set of animal experiments, Nanji’sgroups, as well as Sieber’s group have both shownthat alcohol induced liver disease in rat or Baboon an-imal models is associated with oxidative stress (Nanjiet al., 1994a, 1994b; Lieber et al., 1997; Lieber,1997; Aleynik et al., 1998). For example,Nanji et al.(1994a)used an intra-gastric feeding rat model foralcoholic liver disease, and demonstrated that animalsfed fish oil and ethanol developed the most severeliver injury and had the highest levels of plasmaF2-IsoPs.

The urinary excretion of F2-IsoPs has been mea-sured by two groups in alcoholic hepatitis, and manypatients with alcoholic hepatitis and HRS were in-cluded in our study.Meagher et al. (1999)found thatpatients with alcoholic hepatitis had a 10-fold increaseof urinary F2-IsoPs compared with controls. Similardata were observed by others, and that urinary F2-IsoPexcretion decreased with abstinence from alcohol andclinical improvement (Hill and Awad, 1999; Aleyniket al., 1999). This has led to some studies evaluat-ing the role of anti-oxidants in the treatment of alco-holic hepatitis, although these remain unpublished atpresent.

2.3. Hepatitis C, primary biliary cirrhosis and livertransplantation

The relationship of oxidative stress and severityof cirrhosis was studied byPratico et al. (1998b).In 42 patients with cirrhosis, 100% of patients withChild-Pugh’s C, 74% of Child’s B and 36% of Child’sA were found to excrete levels greater than controlsubjects. More recent studies have shown that patientswith primary biliary cirrhosis or hepatitis C haveincreased urinary levels of F2-IsoPs as measured byELISA (Jain et al., 2002; Aboutwerat et al., 2003). Allof these findings are not surprising. It has been knownfor some time that liver disease is associated with low-ered plasma and tissue concentrations of glutathione,and that vitamin E and C levels are decreased, consis-tent with oxidative stress. A prospective study has alsobeen carried out on oxidative stress and liver trans-plantation (Burke et al., 2002). In this study Burkeand coworkers looked at the urinary dinor-dihydroF2-IsoP metabolite and showed that urinary levelswere increased significantly following reperfusion of


the grafted liver and levels fall off sharply follow-ing liver transplantation but never reached the basallevel observed in control subjects. These authors con-cluded that liver transplant recipients exhibit enhancedlipid peroxidation in vivo, which is increased duringintra-operative liver perfusion. However and moreimportantly they also observed that urinary excretionof the isoprostane metabolite increased significantlyover time suggesting oxidative stress occurs in posttransplant recipients even in the absence of adverseevents such as cellular rejection. These data mayhave implications for the treatment of liver transplantrecipients in the long term.

2.4. Animal models of liver disease

2.4.1. Iron overloadFrei’s group were the first to demonstrate that

increased iron overload led to a moderate but signifi-cant increase in hepatic F2-IsoP levels whereas therewas no significant change in plasma isoprostanes(Dabbagh et al., 1994). Iron overload was also asso-ciated with a significant decrease in the concentra-tions of alpha-tocopherol and ascorbic acid in plasmaas well as alpha-tocopherol, ubiquinone and betacarotene in the liver. More recently, the same grouphave looked at iron loaded guinea pigs which werefed either a diet that was low in ascorbic acid or highin ascorbic acid (Chen et al., 2000). They observedthat iron loaded animals fed low ascorbate diet haddecreased plasma levels of alpha-tocopherol and in-creased plasma concentrations of F2-IsoPs. In contrastanimals that were fed a high ascorbate diet had sig-nificant lower hepatic F2-IsoPs than the low ascorbicgroup irrespective of iron load. These data suggestthat ascorbic acid can act as an antioxidant in vivoeven in the presence of iron overload. These studiesare important because several in vitro studies haveshown that ascorbic acid can be a pro-oxidant in vitroin the presence of iron. More recently,Salahudeenet al. (2001)have shown that infusion of intravenousiron dextran to levels that sufficiently exceed thesaturation capacity of transferrin results in a smallbut significant increase in esterified F2-IsoPs but nosignificant change in free F2-IsoP concentrations.

Thus, in conclusion despite the misgivings of manythat the concentrations of free iron generated in vivoare likely to be so small as to be irrelevant in generating

lipid peroxidation, studies of iron loaded animals andindeed humans infused with iron dextran suggest thatthese reactions can occur albeit to a modest degree.

2.5. Carbon tetrachloride

As mentioned already, the first demonstration thatlipid peroxidation generated F2-IsoPs was made usingthe carbon tetrachloride model of lipid injury (Morrowet al., 1992a). Carbon tetrachloride is metabolisedthrough a cytochrome P450 enzyme in liver to thetrichloroethyl radical which can initiate lipid peroxi-dation of unsaturated lipids. As might be expected anagent which induces cytochrome P450 can enhancethe cytotoxicity or hepatotoxicity of carbon tetrachlo-ride and agents which deplete the liver of cellularglutathione concentrations will also enhance liverinjury. As shown inFig. 1, administration of carbontetrachloride leads to rapid increase in the amount ofesterified F2-IsoPs in the liver and this is followed bygradual release into plasma. Subsequently, evidenceof liver injury is evident by an increase in plasmatransaminse activity (data not shown). As shown inFig. 4, administration of phenobarbitone or buthionine

Fig. 4. Pretreatment of rats with BSO, which depletes body storesof glutathione causes a considerable enhancement of liver injuryin rats administered carbon tetrachloride (fromAboutwerat et al.,2003).


sulfoximine (BSO) which causes depletion of hep-atic glutathione stores both enhance the generationof F2-IsoPs as well as liver injury caused by carbontetrachloride.

2.6. Ischemia reperfusion injury

The pathophysiological importance of reactiveoxygen species has been extensively documentedin the pathogenesis of ischaemia reperfusion injuryin many organs including the liver. In one study,Jaeschke’s group showed that during 45 min of hep-atic ischaemia and reperfusion that there was up toa 250% increase in plasma F2-IsoPs indicative oflipid peroxidation (Mathews et al., 1994). However,in complementary experiments they showed that in-fusion of tert-butyl hydroperoxide into the liver ledto significant liver peroxidation in the absence ofsignificant liver injury. Since this study in 1994,other studies carried out in other organs have shownincreased generation of F2-isoprostanes in a multi-tude of organs including the heart (Delanty et al.,1997).

2.7. Selenium deficiency and diquat poisoning

In one of the early studies on lipid peroxidation invivo, Awad and coworkers addressed the importanceof vitamin E and selenium defence against lipid per-oxidation in vivo. They reared a group of rats thatwere deficient in either vitamin E, selenium or both forabout three months. They observed a five fold increasein plasma F2-IsoPs in rats fed a diet deficient in bothselenium and vitamin E (Awad et al., 1994a,b). In ad-dition, there were significant increases in liver, lung,kidney, heart and skeletal muscle esterified F2-IsoPsin this group. The same group subsequently demon-strated that selenium deficiency exacerbated diquat in-duced hepatic and renal toxicity in rodents (Atkinsonet al., 2001). They showed that selenium deficiencyand also glutathione deficiency induced by administra-tion of BSO enhances diquat induced injury. It seemsthat diquat induces hepatic necrosis in the presence ofselenium deficiency and in a separate group of stud-ies they demonstrated that there was a gradient ofF2-isoprostane detected across the liver indicating thatthe liver was the main source of circulating plasmaF2-IsoPs.

2.8. Halothane hepatitis

Halothane can be reductively metabolized to freeradical intermediates, which can lead to lipid peroxi-dation. However the role of halothane inducing oxida-tive liver injury had always been speculated but neverproven. However, exposure of rats to halothane led toa 4–11-fold increase in plasma and liver F2-IsoPs, re-spectively, and that this is enhanced when rats werepre-treated with phenobarbitone, which increases themetabolism of halothane through a P450-dependentpathway (Awad et al., 1996).

3. Isoprostanes as biological mediators

F2-IsoPs possess potent biological activity and maybe important mediators for some of the adverse effectsof oxidant injury.

3.1. Effects on membrane function

When F2-IsoPs are formed as esterified complexesin phospholipids there is a marked distortion of themembrane (Morrow et al., 1992a), leading to changesin membrane fluidity, integrity, and function. However,there have not been any studies to directly addresswhether this occurs in practice.

3.2. Receptor-mediated biological actions

Two IsoPs have been available for biological test-ing are 15-F2t-IsoP (8-iso-PGF2) and 15-E2t-IsoP(8-iso-PGE2), and these differ from their respectivecyclo-oxygenase-derived counterparts by inversion ofthe upper side chain stereochemistry. Both 15-F2t-IsoPand 15-E2t-IsoP are produced in vivo, and both havebeen shown to be potent vasoconstrictors in a varietyof vascular beds including the kidney (Morrow et al.,1992b), portal venous system, coronary (Kromer andTippins, 1996; Reilly et al., 1997; Wilson et al., 1999),retina (Michoud et al., 1998; Lahaie et al., 1998; Houet al., 2001), lung (Christman and Bernard, 1993; Hillet al., 1997; Janssen et al., 2001), cerebral microcir-culation (Brault et al., 2003), and also the lymphatics(Sinzinger et al., 1997). In addition, 15-F2t-IsoP in-duces endothelin release and proliferation of vascularsmooth muscle cells (Fukunaga et al., 1995; Yura


et al., 1999; Ruef et al., 2001). Results from initialexperiments suggested that the vascular effects ofboth of these IsoPs may result from an interactionwith thromboxane receptors based on the finding thatthe vasoconstriction could be abrogated by thrombox-ane receptor antagonists. However, a number lines ofevidence obtained subsequently suggests that theseIsoPs may not interact with thromboxane receptors(Fukunaga et al., 1993, 1997). Whether these IsoPsmediate their effects by interaction with some otherknown receptor(s) or a novel isoIsoP receptor(s), itremains to be determined.

3.3. Mediators of renal vasoconstriction in thehepatorenal syndrome?

3.3.1. Portal hypertensionInfusion of 8-iso-PGF2� into cirrhotic rats causes

a marked increase in portal pressure (Marley et al.,1997). Cirrhotic rats had a much greater increase inportal pressure than normal animals. Additionally, theresponse was blocked by SQ29548, a thromboxanereceptor antagonist receptor antagonist. This coupledwith the fact that cirrhotic rats form significantlyhigher amounts of F2-IsoPs during endotoxemia(Harry et al., 1999), and that patients with sepsisare more prone to bleed (Goulis et al., 1998, 1999;Montalto et al., 2002) suggests that the both maybe causally related. However,Pratico et al. (1998c)studied plasma and portal F2-IsoPs in eighteen cir-rhotic patients. The majority of these patients had aviral aetiology for their cirrhosis. They found higherlevels of peripheral F2-IsoPs in patients with cir-rhosis compared to controls, consistent with otherstudies. In addition, the concentrations of F2-IsoPs inthe portal venous blood were higher than in the pe-ripheral circulation in the cirrhotic group. However,there was no correlation between portal pressure andplasma F2-IsoP concentrations. In addition, there wasno correlation between F2-IsoP levels and liver dis-ease severity, which this group had earlier reported(Pratico et al., 1998b). Whether F2-IsoPs can affectportal pressure in vivo remains unknown.

4. Conclusion

F2-IsoPs serve as markers of oxidative stress. Ox-idative stress may be responsible for liver damage in a

number of conditions. In some conditions, such as al-coholic liver disease, the degree of oxidative stress, asreflected by levels of F2-IsoPs, may indicate diseaseseverity. F2-IsoPs exist in esterified and free forms.Esterified F2-IsoPs can lead to the loss of structuralintegrity of cell membranes. Free isoprostanes can ex-ert a range of biological activities either directly oras a consequence of releasing other mediators such asendothelin-1, MCP-1 etc.

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isoprostanes and the liver

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