- Open Access
CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction
© Springer-Verlag 2009
- Received: 22 July 2009
- Accepted: 14 September 2009
- Published: 2 October 2009
The mechanisms by which alcohol causes cell injury are not clear. A major mechanism that is the focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFα and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other, however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNF toxicity and that oxidants, such as peroxynitrite, activation of p38 and JNK MAP kinases, inactivation of NF-kB protective pathways and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNF potentiated hepatotoxicity. This review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved.
- Oxidative stress
- Tumor necrosis factor alpha
The ability of acute and chronic ethanol treatment to increase production of reactive oxygen species and to enhance peroxidation of lipids, protein, and DNA has been demonstrated in a variety of systems, cells, and species, including humans . Despite a tremendous growth in understanding alcohol metabolism and actions, the mechanism(s) by which alcohol causes cell injury are still not clear. A variety of leading mechanisms has been briefly summarized [13, 17, 67], and it is likely that many of them ultimately converge as they reflect a spectrum of the organism’s response to the myriad of direct and indirect actions of alcohol. A major mechanism that is a focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a key role in how ethanol induces “oxidative stress”. Some of these include redox state changes (decrease in the NAD+/NADH redox ratio) produced as a result of ethanol oxidation by alcohol and aldehyde dehydrogenases; production of the reactive product acetaldehyde as a consequence of ethanol oxidation by all major oxidative pathways; damage to mitochondria which results in decreased ATP production; direct or membrane effects caused by hydrophobic ethanol interaction with either phospholipids or protein components or enzymes; ethanol-induced hypoxia, especially in the pericentral zone of the liver acinus as oxygen is consumed in order for the liver to detoxify ethanol via oxidation; ethanol effects on the immune system, and altered cytokine production; ethanol-induced increase in bacterial-derived endotoxin with subsequent activation of Kupffer cells; ethanol induction of CYP2E1; ethanol mobilization of iron which results in enhanced levels of low molecular weight non-heme iron; effects on antioxidant enzymes and chemicals, particularly mitochondrial and cytosolic glutathione; one electron oxidation of ethanol to the 1-hydroxy ethyl radical; conversion of xanthine dehydrogenase to the xanthine oxidase form. Again, many of these pathways are not exclusive of one another and it is likely that several, indeed many, systems contribute to the ability of ethanol to induce a state of oxidative stress.
What is the evidence that ethanol-induced oxidative stress plays a role in cell injury? While many studies have shown increases in lipid peroxidation or protein carbonyl formation by alcohol, it is not always clear if these are causes of or consequences of the alcohol-induced tissue injury. Nevertheless, there are many studies, which show that administration of antioxidants or iron chelators or GSH-replenishing agents can prevent or ameliorate the toxic actions of alcohol. The most convincing data that oxidative stress contributes to alcohol-induced liver injury comes from the studies using the intragastric infusion model of alcohol administration. In these studies, alcohol-induced liver injury was associated with enhanced lipid peroxidation, protein carbonyl formation, formation of the 1-hydroxyethyl radical, formation of lipid radicals, decreases in hepatic antioxidant defense especially GSH [35, 39, 63, 65, 87]. Replacement of polyunsaturated fat (required for lipid peroxidation to occur) with saturated fat or medium chain triglycerides in the diets fed to rats intragastrically, lowered or prevented the lipid peroxidation, and the alcohol-induced liver injury. Thus, alcohol plus polyunsaturated fat was required for the injury to occur. Addition of iron, known to generate •OH and promote oxidative stress, to these diets exacerbated the liver injury . Importantly, addition of antioxidants, such as vitamin E, ebselen, superoxide dismutase, GSH precursors prevented the alcohol-induced liver injury.
In addition to these in vivo studies, in vitro studies with hepatocytes also showed that ethanol could produce oxidative stress and hepatocyte toxicity. Studies with isolated hepatocytes from control rats or chronic ethanol-fed rats indicated that ethanol metabolism via alcohol dehydrogenase results in an increase in ROS production, hepatocyte injury, and apoptosis, reactions blocked by antioxidants [1, 9, 47]. Studies in our laboratory with HepG2 cell lines expressing CYP2E1 showed that addition of ethanol or polyunsaturated fatty acids or iron, or depletion of GSH, resulted in cell toxicity, increased oxidative stress, and mitochondrial damage, reactions prevented by antioxidants [94, 95]. HepG2 cells expressing both CYP2E1 and alcohol dehydrogenase have been valuable in studies on ethanol-induced oxidative stress and cell injury [21, 68].
Kupffer cells and alcoholic liver disease
Kupffer cells are stimulated by chronic ethanol treatment to produce free radicals and cytokines, including tumor necrosis factor alpha (TNFα), which plays a role in ALD. [2, 34]. This stimulation is mediated by bacterial-derived endotoxin, and ALD is decreased when Gram-negative bacteria are depleted from the gut by treatment with lactobacillus or antibiotics . The TNFα receptor super-family consists of several members sharing a sequence homology, the death domain, located in the intracellular portion of the receptor. These “death” receptors, including Fas, TNF-R1, and TRAIL-R1/TRAIL-R2 are expressed in hepatocytes and when stimulated by their respective ligands, FasL, TNFα, or TRAIL, hepatocyte injury can occur . Lipopolysaccharide (LPS) is a component of the outer wall of Gram-negative bacteria that normally inhabit the gut. LPS penetrates the gut epithelium only in trace amounts; however, LPS absorption can be elevated under pathophysiological conditions such as alcoholic liver disease . When LPS is released from Gram-negative bacteria and enters the blood stream, the liver tightly regulates the entry and processing of LPS by virtue of its ability to clear LPS and respond to LPS . In addition to its ability to clear LPS, the liver also responds to LPS and produces cytokines. LPS directly causes liver injury by mechanisms involving inflammatory cells such as Kupffer cells, and chemical mediators such as superoxide, nitric oxide, and tumor necrosis factor (TNFα) and other cytokines [31, 81, 91]. In addition, LPS potentiates liver damage induced by hepatotoxins including ethanol [10, 19, 30, 46, 59, 84]. In experimental alcoholic liver disease, the combination of LPS and chronic ethanol produces hepatic necrosis and inflammation [30, 46, 59, 84]. Ethanol alters gut microflora, the source of LPS, and ethanol increases the permeability of the gut, thus increasing the distribution of LPS from the gut into the portal circulation (endotoxemia). This causes activation of Kupffer cells, the resident macrophages in liver, resulting in release of chemical mediators including cytokines and ROS and subsequently, alcoholic liver disease . Destruction of Kupffer cells with gadolinium chloride attenuated ALD . A major advance was the finding that anti-TNFα antibodies protect against ALD . NADPH oxidase was identified as a key enzyme for generating reactive oxygen species (ROS) in Kupffer cells after ethanol treatment . Moreover, in mice deficient in a subunit of NADPH oxidase, p47phox, the ethanol-induced increase in ROS and TNFα and liver injury was decreased . The role of TNFα in ALD was further validated by the findings that the ethanol-induced pathology was nearly blocked in TNFα receptor1 knockout mice .
The transcription factor nuclear factor-kappaB (NF-kB) in Kupffer cells regulates activation of many inflammatory genes, including TNFα. Endotoxin activates NF-kB, leading to the hypothesis that inhibition of NF-kB in Kupffer cells would prevent ALD . Administration of an adenovirus encoding for the IkB superrepressor to rats chronically infused with ethanol blunted the ethanol-induced activation of NF-kB, TNFα production, and pathological changes. A general scheme to explain these results is that chronic ethanol treatment elevates endotoxin levels, endotoxin activates Kupffer cells to produce free radicals via NADPH oxidase, the free radicals activate NF-kB, leading to an increase in production of TNFα, followed eventually by tissue damage [82, 84, 92].
CYP2E1 metabolizes a variety of small, hydrophobic substrates including solvents such as chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene and toluene, alcohols such as ethanol and pentanol, aldehydes such as acetaldehyde, halogenated anesthetics such as enflurane and halothane, nitrosamines such as N,N-dimethylnitrosamine and drugs such as chlorzoxazone and acetaminophen [12, 43, 50, 75, 77, 79, 83, 98]. From a toxicological point of view, interest in CYP2E1 revolves around the ability of this P450 to metabolize and to activate many toxicologically important compounds, such as ethanol, carbon tetrachloride, acetaminophen, benzene, halothane, and many other halogenated substrates. Procarcinogens including nitrosamines and azo compounds are effective substrates for CYP2E1. Toxicity by the above compounds is enhanced after induction of CYP2E1, e.g. by ethanol treatment, and toxicity is reduced by inhibitors of CYP2E1 or in CYP2E1 knockout mice . Chlorzoxazone is of special value as its hydroxylated product can readily be assayed in the blood and the ratio of 6-hydroxychlorzoxazone/chlorzoxazone is widely used to assess the approximate levels of CYP2E1 in humans, including alcoholics .
Molecular oxygen itself is likely to be a most important substrate for CYP2E1 [11, 93]. CYP2E1, relative to several other P450 enzymes, displays high NADPH oxidase activity as it appears to be poorly coupled with NADPH–cytochrome P450 reductase [22, 27]. CYP2E1 was the most efficient P450 enzyme in the initiation of NADPH-dependent lipid peroxidation in reconstituted membranes among five different P450 forms investigated. Furthermore, anti-CYP2E1 IgG inhibited microsomal NADPH oxidase activity and microsomal lipid peroxidation dependent on P450, but not lipid peroxidation initiated by the action of NADPH-cytochrome P450 reductase . In our laboratory, we found that microsomes isolated from rats fed ethanol chronically were about two to threefold more reactive in generating superoxide radical and H2O2, and in the presence of ferric complexes, in generating hydroxyl radical and undergoing lipid peroxidation [20, 38, 71, 74]. CYP2E1 levels were elevated about three to fivefold in liver microsomes after feeding rats the Lieber–DeCarli diet for 4 weeks. In all the above systems, the enhanced effectiveness of microsomes isolated from the ethanol-fed rats was prevented by addition of chemical inhibitors of CYP2E1 and by polyclonal antibody raised against CYP2E1 purified from pyrazole-treated rats, confirming that the increased activity in these microsomes was due to CYP2E1.
Since CYP2E1 can generate ROS during its catalytic cycle, and its levels are elevated by chronic treatment with ethanol, CYP2E1 has been suggested as a major contributor to ethanol-induced oxidant stress, and to ethanol-induced liver injury . Initial suggestions for a role for CYP2E1 in alcoholic liver injury arose from studies with the intragastric model of ethanol feeding, in which prominent induction of CYP2E1 occurs and significant alcohol liver injury occurs [24, 63, 65, 88]. In these models, large increases in microsomal lipid peroxidation have been observed and the ethanol-induced liver pathology has been shown to correlate with CYP2E1 levels and elevated lipid peroxidation [16, 63, 65, 76]. Experimentally, a decrease in CYP2E1 induction was found to be associated with a reduction in alcohol-induced liver injury [25, 37]. CYP2E1 inhibitors such as diallyl sulfide (DAS) , phenethyl isothiocyanate (PIC) [4, 64] and chlormethiazole , blocked the lipid peroxidation and ameliorated the pathologic changes in ethanol-fed rats. Polyenylphosphatidylcholine (PPC), another compound exerting anti-CYP2E1 properties  was effective in opposing alcohol-induced oxidative stress . A strong association between dietary carbohydrate, enhanced CYP2E1 induction, and hepatic necrosis was observed. No liver injury was found if carbohydrate levels were elevated . Ethanol consumption in liquid diets does not cause liver injury. However, micro and macrovesicular steatosis, occasional inflammatory foci and a threefold increase in transaminase levels were observed in a nutritionally adequate ethanol containing liquid diet with a carbohydrate content of 5.5%; no changes were found if the level of carbohydrate was elevated to 11% [49, 52]. Thus, dietary and nutritional factors play a key role in the toxic actions of ethanol to the liver, in part, due to modulation of the levels of CYP2E1. A CYP2E1 transgenic mouse model was developed that overexpressed CYP2E1. When treated with ethanol, the CYP2E1 overexpressing mice displayed higher transaminase levels and histological features of liver injury compared with the control mice . We developed an adenoviral vector, which expresses human CYP2E1 and showed that infection of HepG2 cells with this adenovirus potentiated acetaminophen toxicity as compared to HepG2 cells infected with a LacZ expressing adenovirus . Administration of the CYP2E1 adenovirus in vivo to mice elevated CYP2E1 levels and activity and produced significant liver injury compared to the LacZ-infected mice as reflected by histopathology and elevated transaminase levels .
On the other hand, studies by Thurman and colleagues have presented powerful support for a role for endotoxin, activation of Kupffer cells and cytokines such as TNFα in the alcohol-induced liver injury found with the intragastric infusion model [92, 100]. They suggested that CYP2E1 may not play a role in alcohol liver injury based upon studies with gadolinium chloride or CYP2E1 knockout mice [40, 44]. However, as discussed elsewhere [56, 85], induction by ethanol of other CYPS or of the reductase in the CYP2E1 knockout mice might have served as alternative sources of oxidative stress in these mice, especially in the absence of CYP2E1. Bradford et al.  using CYP2E1 and NADPH oxidase knockout mice concluded that CYP2E1 was required for ethanol induction of oxidative stress to DNA, whereas NADPH oxidase was required for ethanol-induced liver injury. Clearly, further studies are necessary to resolve the above discrepancies. As mentioned earlier, it is likely that several mechanisms contribute to alcohol-induced liver injury, and that ethanol-induced oxidant stress is likely to arise from several sources, including CYP2E1, mitochondria, and activated Kupffer cells.
As discussed above abnormal cytokine metabolism is a major feature of alcoholic liver disease. Rats chronically fed ethanol were more sensitive to the hepatotoxic effects of administration of LPS and had higher plasma levels of TNFα than control rats [33, 36]. In the intragastric model of chronic ethanol administration, the development of liver injury coincided with an increase in TNFα, associated with an increase in serum LPS . Anti-TNFα antibody prevented alcohol liver injury in rats  and mice lacking the TNFR1 receptor did not develop alcohol liver injury . Taken as a whole, these and other studies clearly implicate TNFα as a major risk factor for the development of alcoholic liver injury. One complication in this central role for TNFα is that hepatocytes are normally resistant to TNFα induced toxicity. This led to the hypothesis that besides elevating TNFα, alcohol somehow sensitizes or primes the liver to become susceptible to TNFα [72, 86]. Known factors which sensitize the liver to TNFα are inhibitors of mRNA or protein synthesis, which likely prevent the synthesis of protective factors, inhibition of NF-κB activation in hepatocytes to lower synthesis of such protective factors, depletion of GSH, especially mitochondrial GSH, lowering of S-adenosyl methionine (SAM) coupled to elevation of S-adenosyl homocysteine (SAH), i.e. a decline in the SAM/SAH ratio, or inhibition of the proteasome. Combined treatment with ethanol plus TNFα is more toxic to hepatocytes and HepG2 E47 cells which express high levels of CYP2E1 than control hepatocytes with lower levels of CYP2E1 or HepG2 C34 cells which do not express CYP2E1 . RALA hepatocytes with increased expression of CYP2E1 were sensitized to TNFα mediated cell death . These results suggest that increased oxidant stress from CYP2E1 may sensitize isolated hepatocytes to TNFα-induced toxicity.
Either LPS or CYP2E1 are considered independent risk factors involved in alcoholic liver disease, but mutual relationships or interactions between them are unknown. Toxic interactions between CYP2E1 and TNFα have been reported in vitro [53, 54, 69, 70] and it would be of importance to evaluate whether CYP2E1 contributes or potentiates LPS- mediated liver injury in vivo. The overall objective of the rest of this review is to explore the susceptibility and possible synergistic effect of CYP2E1 overexpression on LPS and TNF hepatotoxicity. These studies may provide an experimental model to better understand mechanisms of ethanol-induced liver damage.
To assess whether oxidative stress occurs after the various treatments, malondialdehyde (MDA) levels as a reflection of lipid peroxidation, were assayed. Whereas pyrazole alone or LPS alone did not elevate MDA levels over those found with saline controls, the combination of LPS plus pyrazole increased MDA levels about 65% (p < 0.05 compared to the other 3 groups). Protein carbonyl formation as a marker for oxidized protein formation was determined. Low levels of protein carbonyls were found in saline control livers. Either treatment with LPS alone or pyrazole alone elevated protein carbonyl levels, however, striking increases in protein carbonyls were found in the combined LPS plus pyrazole group. In situ detection of superoxide was measured using the oxidation-dependent fluorescent dye dihydroethidum. Red fluorescence was weak in saline control livers, was slightly increased in either the LPS or pyrazole livers, and was highest in the LPS plus pyrazole livers. 3-Nitrotyrosine (3-NT) protein adducts were detected by a slot blot technique. 3-NT adducts were highest in livers from the LPS plus pyrazole treated mice. Thus, several parameters of oxidative/nitrosative stress were elevated in livers from the LPS plus pyrazole-treated mice.
CYP2E1 catalytic activity (oxidation of P-nitrophenol to p-nitrocatechol) was increased about twofold by the pyrazole alone or the pyrazole plus LPS treatments. LPS alone slightly decreased CYP2E1 activity but not significantly. Levels of CYP2E1 protein, measured by immunoblot analysis, showed similar trends, being increased about twofold by pyrazole or pyrazole plus LPS treatments. These results show that pyrazole treatment enhanced LPS-induced necrosis, not apoptosis. This enhanced liver injury is associated with elevated levels of CYP2E1 and increased oxidative/nitrosative stress generated by the combination of LPS plus elevated CYP2E1.
Pyrazole potentiates TNFα toxicity 
Since TNFα levels are elevated after LPS administration and TNFα plays an important role in the effects of LPS, we determined if pyrazole treatment to induce CYP2E1 potentiates TNFα toxicity as it did LPS toxicity. Basically, the same approaches described above were used, with injection of TNFα (50 μg/kg body wt.) replacing the LPS treatment.
Activation of MAP kinases
The electrochemical potential of the proton gradient generated across the mitochondrial membrane (ΔΨ) was assessed by monitoring fluorescence quenching of rhodamine 123. Addition of 10 mM succinate at 1 min caused a decrease in fluorescence reflective of a high ΔΨ corresponding to state 4 of respiration (Fig. 7). The decline in fluorescence averaged about 40 arbitrary units per minute with mitochondria from the saline or TNFα alone treated mice and 30 arbitrary units per minute with mitochondria from the pyrazole-treated mice. However, the decline in fluorescence was only about 14 arbitrary units with mitochondria from the TNFα plus pyrazole-treated mice. Addition of ADP at 3 min caused an enhancement of fluorescence which corresponds to state 3 respiration as part of the proton motive force is utilized to synthesize ATP. This enhancement of fluorescence averaged 15, 14, 12, and 4 arbitrary units per minute for mitochondria from the saline, TNFα alone, pyrazole alone and TNFα plus pyrazole treated mice, respectively. Taken as a whole, these initial data suggest a small decline in ΔΨ in mitochondria from the pyrazole-treated mice and a more pronounced decline in mitochondria from the pyrazole plus TNFα-treated mice.
TNF-R1 and c-FLIP protein levels
TNF-R1 is a cell surface molecule which initiates the majority of TNFα’s activities. c-FLIP acts as a caspase-8 dominant negative regulator, blocking apoptosis. The levels of TNF-R1 and c-FLIP were determined in mice treated with saline, TNFα alone, pyrazole alone or TNFα plus pyrazole. There were no differences in the levels of TNF-R1 among these four groups; thus, induction of CYP2E1 does not potentiate TNFα hepatotoxicity by changing TNF-R1 levels. However, we did not observe significant liver injury when pyrazole plus LPS was given to TNF R1 knockout mice, indicating that TNFα binding to TNF-R1 is required to initiate the signaling leading ultimately to the liver injury. Levels of both c-FLIPL and c-FLIPs were lower in pyrazole alone- and pyrazole plus TNFα-treated mice compared to saline- and TNFα alone-treated mice. Decreasing c-FLIP by pyrazole induction of CYP2E1 may be one of the possible mechanisms by which CYP2E1 potentiates TNFα induced liver injury. We suggest that although pyrazole alone lowers c-FLIP, little toxicity is found with pyrazole alone in the absence of TNFα i.e. 2 hits are necessary for liver injury. This decline in c-FLIP could be suggestive of a decline in NF-κB signaling and activation since c-FLIP is a NF-κB regulated gene.
NF-κB activation pathway 
Effect of N-acetylcysteine (NAC)
Chronic ethanol treatment 
Pyrazole/TNFα hepatotoxicity in iNOS knockout mice
Cyclosporine A (CsA) prevents pyrazole plus LPS-induced liver injury 
This review has focused on two major contributors to mechanisms by which ethanol causes liver injury, induction of CYP2E1 and elevated endotoxin (LPS) levels followed by increased production of TNFα. Each of these has been extensively studied but there are few studies in which both factors have been evaluated simultaneously. We have shown that induction of CYP2E1 by pyrazole potentiates LPS- or TNF-induced hepatotoxicity. Evidence for a role for CYP2E1 comes from studies in which the CYP2E1 inhibitor CMZ blocks the liver injury, and from studies with CYP2E1 knockout mice where pyrazole plus LPS toxicity is blunted. The potentiated toxicity is associated with an increase in oxidative and nitrosative stress. Prevention of such increases, e.g. treatment with the antioxidant NAC or administration of TNFα plus pyrazole to iNOS knockout mice blunts the liver injury thus validating that the elevated oxidative/nitrosative stress plays a key role in producing the liver injury rather than occurs because of liver injury. JNK and P38 MAP kinases are activated by the combined pyrazole plus LPS/TNFα treatment. Preventing activation of JNK with SP600125 or activation of P38 MAPK with SB203580 decreases the liver injury. Inhibition of CYP2E1 or use of CYP2E1 knockout or iNOS knockout mice or preventing the oxidative/nitrosative stress decreases the activation of JNK and P38 MAPK.
TNFα toxicity in hepatocytes is usually mitigated by activation of NF-kB protective factors. However, the TNFα activation of NF-kB is lost in the TNFα plus pyrazole treated mice with a subsequent decline in protective factors such as MnSOD. We hypothesize that the increase in oxidative/nitrosative stress, the decline in NF-kB protection, and the activation of MAPkinases ultimately affect mitochondrial integrity and function as shown by the increase in mitochondrial swelling and decline in mitochondrial membrane potential. Protection of mitochondrial integrity, e.g. with CsA, prevents the TNFα plus pyrazole hepatotoxicity.
Future studies are planned to evaluate molecular mechanisms for the activation of JNK and P38 MAPK, e.g. assaying MAPKK and MAPKKK, especially ASK-1 which is activated when ROS promote disassociation of the inhibitory thioredoxin; assaying MAPK phosphatases which are very sensitive to inhibition by ROS; evaluating whether there is a switch in toxicity from an initial apoptosis to necrosis as oxidative stress and impairment of mitochondrial function intensify. LPS toxicity was also increased by chronic ethanol consumption in wild type mice but not in CYP2E1 knockout mice. Future studies are planned to evaluate the role of CYP2E1 in ethanol potentiation of LPS/TNFα hepatotoxicity, following what has been learned in the pyrazole model with respect to roles of oxidative/nitrosative stress, iNOS, NF-kB, MAPK and mitochondrial dysfunction.
Research conducted by the authors was supported by grants from The National Institute on Alcohol Abuse and Alcoholism/NIH.
Conflict of interest statement
Nothing to declare.
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