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Changes in Activities of MMP in Alcohol and Thermally Oxidized
Sunflower Oil-Induced Liver Damage: NAC Antioxidant TherapySuresh Varma Penumathsa a; Aruna Kode a; Rukkumani Rajagopalan a; Venugopal P. Menon a
a Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar, India
To cite this Article Penumathsa, Suresh Varma, Kode, Aruna, Rajagopalan, Rukkumani and Menon, Venugopal P.(2006)'Changes in Activities of MMP in Alcohol and Thermally Oxidized Sunflower Oil-Induced Liver Damage: NACAntioxidant Therapy', Toxicology Mechanisms and Methods, 16: 5, 267 — 274
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Toxicology Mechanisms and Methods, 16: 267–274, 2006
Copyright c Taylor & Francis Group, LLC
ISSN: 1537-6524 print / 1537-6516 online
DOI: 10.1080/15376520500194734
Changes in Activities of MMP in Alcohol and ThermallyOxidized Sunflower Oil-Induced Liver Damage: NAC
Antioxidant TherapySuresh Varma Penumathsa, Aruna Kode, Rukkumani Rajagopalan, andVenugopal P. Menon Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar-608 002, India
Liver fibrosis is the result of imbalance between extracellularmatrix (ECM)synthesisand breakdown. Ethanol-induced increasein redox state is a sign of major change in hepatic metabolism andthis inhibits tricarboxylic acid cycle activity and, fatty acid oxida-tion and increases fatty acid uptake, thus predisposing fatty liver.Fibrotic changes induced by alcohol are provoked by diets rich inPUFA. Heating of oils rich inPUFA produces toxicvolatileand non-volatile compounds, which aggravate liver damage. Hepatotoxicitywas induced in male Wistar rats by administering alcohol (20%)and thermally oxidized sunflower oil (PUFA) (15%). When N-acetyl cyteine (NAC) (150 mg/kg body weight), an ROS scavenger,was administered, there was a reversal of liver damage, which wasdemonstrated biochemically. Matrix metalloproteinases (MMPs),being potential biochemical indicators of fibroproliferation, wereestimated in the present study, which were found to be altered inalcohol, PUFA, and alcohol +PUFA. The altered activities of MMPs in these groups were effectively modulated by treatmentwith NAC. Thus, in this study, NAC was found to modulate the
effect of alcohol and PUFA-induced liver damage.
Keywords NAC, Matrix Metalloproteinases, Alcohol, PUFA
INTRODUCTION
In alcoholic liver disease, liver fibrosis is considered as a first
step, followed by severe fibrotic changes, which lead eventually
to cirrhosis. Hepatic fibrosis is the result of imbalance between
enhanced matrix synthesis and breakdown of connective tissue
proteins, the net result of which is increased deposition of ECM.
All routes of ethanol oxidation result in formation of acetalde-
hyde. Ethanol as well as its metabolite acetaldehyde have been
involved in the stimulation of collagen synthesis (Niemala et al.1995). Brenner and Chojkier (1987) were the first to report that
acetaldehyde increased collagen gene transcription in cultured
Received 7 January 2005; accepted 7 July 2005.Address correspondence to Dr. Venugopal P Menon, Professor
and Head, Department of Biochemistry, Annamalai University,Annamalainagar – 608 002, Tamil Nadu, India. E-mail:cdl [email protected]; [email protected]; [email protected]
fibroblasts. Lieber and colleagues thereafter made an important
observation that acetaldehyde stimulates collagen gene activa-
tion and protein synthesisin hepatic stellate cells (Moshageet al.
1990).The composition of dietary fat is reflected in the composition
of the lipids accumulating in the liver of ethanol-fed animals.
It is also suggested that the more fat in the liver, the higher the
susceptibility to severe damage (Day and James 1998). The pro-
portion of unsaturated fat correlates with the damage. Diets rich
in PUFA have influenced the development of liver injury (Nangi
et al. 1994). Thermal oxidation of oil produces volatile and non-
volatile compounds, leading to variety of diseases (Twefix et al.
1998). Enhanced liver damage has been shown when thermally
oxidized sunflower oil (PUFA) is supplemented along with
ethanol (Rukkumani et al. 2002; Aruna et al. 2002).
During severe damage, fibrotic changes occur in the liver,
which is characterized by proliferation of hepatic stellatecells and their transformation into myofibroblasts. Hepatic
myofibroblasts are the source of the overproduction of structural
proteins that constitute liver fibrosis (Friedman 1999). Several
biochemical indicators have been shown as potential markers
of fibroproliferation. Among them, MMPs have been shown
by several groups to correlate more or less closely with the de-
velopment of fibrosis. MMPs are zinc- and calcium-dependent
enzymes that are largely responsible for degrading ECM
components (Mignatti and Rifkin 1993). MMPs digest specific
ECM components during abnormalities and thereby contribute
to matrix equilibrium and structural integrity.
NAC, a reactive oxygen species (ROS) scavenger, is a deriva-
tive of L-cysteine and is present in higher amounts in protein-
rich foods. NAC acts as a source of cysteine and stimulates the
production of GSH, which protects the body. It has antioxidant,
anti-inflammatory, and hypolipidemic properties (Devries and
De Flora 1993). Thiol compounds such as cysteine are known
to increase the survival rate of alcohol-fed rats (Rajakrishnan
et al. 1997) and have been found to be an effective antidote for
acetaldehyde poisoning and an antagonist to hepatotoxic effect
of carbon tetrachloride (Jaya et al. 1994). NAC has also been
267
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268 S. V. PENUMATHSA ET AL.
shown to protect the liver from the adverse effects of several
toxic chemicals (Ben et al. 2000). The purpose of our study is to
find the effect of NAC on the synthesis and activities of MMPs
during alcohol- and PUFA-induced toxicity.
MATERIALS AND METHODS
Maintenance of AnimalsMale albino Wistar rats of body weight ranging from 140
to 150 g bred in Central Animal House, Rajah Muthiah Medi-
cal College, Annamalai University, were fed on pelletdiet (Agro
Corp. Pvt. Ltd., Bangalore, India)and water ad libitum. Thestan-
dard pellet diet comprised 21% proteins, 5% lipids, 4% crude
fiber, 8% ash, 1% calcium, 0.6% phosphorous, 3.4% glucose,
2% vitamins, and 55% carbohydrates and provided metaboliz-
able energy of 3600 kcal/kg. The animals were housed in plastic
cages under controlled condition of 12-h light/12-h dark cycle,
50% humidity, and 30 ± 3◦C. The animals used in the present
study were maintained in accordance with the guidelines of the
National Institute of Nutrition, Indian Council of Medical Re-
search, Hyderabad, India, and approved by the Animal Ethical
Committee, Annamalai University.
Materials Used
1. Ethanol: Absolute ethanol (AR) was obtained from
Hayman Limited, England.
2. Sunflower oil: Sunflower oil marketed by Gold Winner
was purchased from the local market, Chidambaram,
Tamil Nadu, India.
3. NAC: N-acetyl-L-cysteine was purchased from Sigma
Chemical Company, USA.
4. Thermally oxidized sunflower oil (PUFA): Sunflower
oilwas subjectedto heating at 180◦
C for30 minutes, twice(fatty acid composition is shown in Table 1) (Aruna et al.
2002).
All other chemicals used were of analytical grade.
Experimental Design
Normal : Control rats given standard pellet diet
Alcohol : Rats given 20% ethanol [7.9 g/kg body weight]
(Rajakrishnan et al. 1997)
PUFA : Rats given high-fat diet (15%) (thermally oxidized
sunflower oil mixed with diet) (Aruna et al. 2002)
Alcohol+PUFA : Rats given 20% ethanol orally using an in-
tragastric tube and a high-fat diet (15%) (thermally oxidizedsunflower oil mixed with diet)
Alcohol + NAC : Rats given NAC (150 mg/kg body weight)
dissolved in 20% ethanol
PUFA+ NAC : Rats given NAC dissolved in water and high-
fat diet (15%) (thermally oxidized sunflower oil mixed with
diet)
Alcohol+PUFA+NAC : Rats given NAC dissolved in alco-
hol and high-fat diet (15%) (thermally oxidized sunflower
oil mixed with diet)
TABLE 1
Fatty acid composition of sunflower oil and heated
sunflower oil percentage of fatty acid/g oil
Fatty acid Sunflower oil Heated sunflower oil
9:0 3OH — 0.27± 0.02
10:0 1.10± 0.08 0.15± 0.0110:0 2OH — 0.34± 0.03
10:0 3OH — 0.15± 0.01
11:0 — 4.27± 0.39
12:0 5.74± 0.53 2.02± 0.18
13:0 0.76± 0.05 —
14:0 1.11± 0.06 0.25± 0.02
15:0 0.49± 0.04 0.30± 0.02
16:0 17.93± 1.54 16.78± 1.59
16:1 — 0.36± 0.03
17:0 — 0.67± 0.05
17:0 cyclo — 0.52± 0.04
18:0 9.87± 0.85 9.92± 0.87
18:1 60.22± 5.74 52.89± 4.6518:1 2OH — 1.82± 0.13
19:0 2.17± 0.19 0.95± 0.05
20:0 0.61± 0.04 1.56± 0.08
20:1 — 6.78± 0.65
NAC : NAC 150 mg/kg body weight (Jaya et al. 1994) dissolved
in water.
All animals were maintained on isocalorific diet using glu-
cose solution (total calories/day: 508 kcal/kg body weight). At
the endof experimental period (45 days), therats were sacrificedafter an overnight fast by decapitation. The liver was removed,
cleared of blood, and immediately transferred to ice cold con-
tainers containing 0.9% NaCl for various estimation.
Methods
1. Multiwellzymography:It was done by themethod Ambili
and Sudhakaran (1998).
2. SDS-PAGE zymography: It was done by the method of
Ambili et al. (1997). Gelatin substrate-impregnated SDS-
polyacrylamide gels were used. Samples were separated
according to their molecular weight by electrophoresis.
3. Succinylation: It was done by the method of Vijaykumaret al. (Baragi et al. 2000) for the quantitative estimation
of MMPs activity.
Statistical Analysis
The data given in the tables are average± standard deviation
(SD). Data were analyzed statistically by “analysis of variance”
(ANOVA) and groups were compared by Duncan’s Multiple
Range Test (DMRT).
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MMPS IN LIVER DAMAGE 269
1
2
FIGS. 1 & 2. Multiwell zymogram of Liver.
RESULTS AND DISCUSSION
Figs. 1, 2, and 3 show the total activities of MMP by mul-
tiwell zymography. Figs. 4 to 7 show the individual activities
of MMP by zymography. The overall MMP activities as evi-
denced by multiwell zymography and individual MMP activities
as seen in zymography were increased significantly in alcohol-
and PUFA-administered rats and decreased significantly in
alcohol + PUFA-treated rats. Administration of NAC posi-tively modulated these activities. The changes in the activities
of MMP-2 and MMP-9 by succinylation alsocorrelate withthese
results (Figs. 8 and 9).
The increase in the activities of MMPs in alcohol and
PUFA groups may be because of the counterbalancing action
of these enzymes to degrade the excessive collagen deposited
(Fig.10). Ingestion of ethanol induces various processes in-
cluding changes in NAD+ /NADH (Arthur 1995), production
of acetaldehyde protein adducts (Lieber 2000), induction of
CYP2El (Tuma et al. 1996), formation of 1-hydroxyethyl free
radicals (Gouillon et al. 2000), and endotoxin-derived activa-
tion of Kupffer cells, which in-turn produce tumor necrosis fac-
tor (Yin et al. 1994). These changes cause severe damage to
the liver. Moreover, acetaldehyde, the main product of ethanol
metabolism, affects hepatic collagen synthesis, both in vivo and
in vitro, leading to increased collagen accumulation, resulting
in fibrosis (Lieber 1993). In PUFA-treated rats, the increased
intake of PUFA increases the degree of unsaturation of the
biomembrane and makes them more susceptible to lipid peroxi-
dation (Farrel and Jackson 1997). Reports have shown that wide
utilization of fats, which are highly susceptible to oxidation dur-
ing cooking and frying, may alter physiological effects of their
PUFA content and generate lipid peroxides that cause mem-
brane damage and increase lipid infiltration predisposing fatty
liver and fibrosis (Jethmalani et al. 1998). Thus, these changes
during alcohol and PUFA ingestion damage the liver and per-
turb the homeostasis of ECM. Furthermore, cyclooxygenase,
lipoxygenase, and cytochrome P450 monooxygenase pathways
are also activated by PUFA, which may increase liver damage
by enhanced production of free radicals, resulting in fibrosis
(Herrera et al. 2001).
Two possible explanations can be given for the increased
activities of MMPs during alcohol and PUFA ingestion. First,
MMP expression may be induced by increased amount of matrix
proteins with compensatory or homeostatic mechanism against
excessive deposition of matrix components. Second, the in-
creased transforming growth factor (TGF) -β1, which is known
to be increased in chronically diseased liver, may upregulate
MMPs at transcriptional and posttranscriptional levels (Overall
et al. 1991). Previous studies have shown that MMPs are up-
regulated in the early phase of experimental liver injury (Mehde
et al. 1997). The MMPs degrade the basal membrane collagenandthus reduceorgan fibrosis. Preauxet al.haveobserved thein-
creased MMP-2 mRNA expressions during liver injury (Preaux
et al. 1999). Moreover, the hepatic mRNA expression for MMP-
2 and MMP-7 are found to be higher in fibrotic patients than
in normal subjects (Lichtinghagen et al. 1999). Expression of
MMP-2 and MMP-7 increases in the early stages of liver tox-
icity and allows an assessment of the amount of a connective
tissue deposited. Thus, the increase in the activities of MMPs in
our study suggests that alcohol and PUFA intake might have
caused significant deposition of connective tissue due to liver
damage.
Previous studies suggest that the ROS activate MMP
(Rajagopalan et al. 1996). During alcohol and PUFA intakethere is an increase in the ROS levels, and this in turn con-
verts inactive zymogen to the active form. Treatment with NAC
brought back the activities of MMPs to near normal. NAC is
widely used as an antioxidant as it scavenges ROS. Previous
studies suggest that scavenging ROS prevent or diminish the
activation of MMP (Devaraj et al. 1996). In the present study,
when NAC was administered, the MMP activities were brought
back to near normal. This may be due to the decreased activation
of MMP zymogen because of decreased ROS levels.
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270 S. V. PENUMATHSA ET AL.
FIG. 3. Densitometry of Liver Multiwell Zymogram.
FIG. 4. Changes in the activities of Matrix Metalloproteinases in liver.
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MMPS IN LIVER DAMAGE 271
FIG. 5. Densitometry of liver zymogram.
In our study the activities of MMPs were found to be de-
creased in the alcohol + PUFA group. Previous reports have
shown that fibrotic changes in rats fed ethanol can be pro-
voked with dietary manipulation (French et al. 1998). A high-fat
ethanol diet has been reported to cause excessive centrilobu-
lar fibrosis within a short period. Previous studies have also
demonstrated that there is a decrease in the interstitial collage-
nase [MMP] activities in late progressive steps of liver fibrosis
(Lichtinghagen et al. 2001). The possible explanation for this
failure of matrix degradation includes decreased procollagenase
gene expression and biosynthesis, decreased activation of proen-
zyme, or specific inhibition of native collagenase. Reports also
FIG. 6. Changes in the activities of Matrix Metalloproteinases in liver.
show increased collagenase activity in early stages and reduced
activity in advanced stages of liver fibrosis (Isao et al. 2001),
which correlate with our findings.
Administration of NAC improved the activities of MMPs
in this group. This might be because of the hepatoprotective
role of NAC. NAC being an effective antioxidant decreases the
damage to the liver and decreases the extent of fibrosis. Previous
reports have also shown that treatment with NAC modulates the
secretion of MMP-9 during atherosclerosis (Galis et al. 1998).
Thus our results show that NAC is an effective antioxidant
and plays a main role in maintaining the architecture of the
liver. NAC prevents the accumulation of ECM components and
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272 S. V. PENUMATHSA ET AL.
FIG. 7. Densitometry of liver zymogram.
FIG. 8. Changes in the activities of MMP-2.
FIG. 9. Changes in the activities of MMP-9.
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MMPS IN LIVER DAMAGE 273
FIG. 10. Mechanism of induction of MMP by Alcohol & PUFA—
Therapeutic role of NAC.
maintains the structural integrity by quenching the ROS pro-
duced during alcohol and heated PUFA intake, thus maintaining
the activities of MMP.
REFERENCESAmbili, M., Radhakrishna, P. M., and Sudhakaran, P. R. 1997. Characteristicsof
60K gelatinase involved in rat mammary gland involution. Ind. J. Biochem.
Biophys. 34:347–353.
Ambili, M., and Sudhakaran, P. R. 1998. Assay of matrix metalloproteinases in
substrate impregnated gels in multiwells. Ind. J. Biochem. Biophys. 35:317–
320.
Arthur, M. J. P. 1995. Collagenase and liver fibrosis. J. Hepatol. 22:43–48.
Aruna, K., Kalpana, C., Viswanathan, P., and Menon, V. P. 2002. Toxic effects
of sunflower oil on ethanol treated rats. Hepatol. Res. 24:125–135.
Baragi, V. M., Shaw, B. J., Renkiewicz, R. R., Kuipers, P. J., Welgus, H. G.,
Mathrubutham, M., Cohen, J. R., and Rao, S. K. 2000. A versatile assay for
gelatinases using succinylated gelatin. Matrix Biol. 19:267–273.
Ben, A. Z., Vaknain, H., and Jur, K. R. 2000. N-acetyl cysteine in acute hepatic
failure (non paracetamol induced). Hepato. Gastroenterol. 47:786–789.
Brenner, D. A., and Chojkier, M. 1987. Acetaldehyde increases collagen
gene transcription in cultured human fibroblasts. J. Biol. Chem. 262:17690–
17695.
Day, C. P., and James,O. F. 1998. Hepatic steatosis: innocent bystanderor guilty
party? Hepatol. 27:1463–1466.
Devaraj, S., Li, D., and Jailal, I. 1996. The effects of alpha tocopherol supple-mentationon monocyte function:decreasedlipid oxidation, interluekin 1 beta
secretion,and monocyteadhesion toendothelium. J.Clin. Invest.98:756–763.
Devries, N., and De flora, S. 1993. N-acetyl-L-cysteine. J. Cell Biochem.
176:270–277.
Farrel, S. O., and Jackson, M. J. 1997. Dietary PUFAs vitamin E and hypoxia/
reoxygenated – induced damage to cardiac tissue. Clin. Chem. Acta.267:197–
211.
French, S. W., Miyamoto, K., Wong, K., Jui, L., and Briere, L. 1988. Role of the
Ito cell in liver parenchymal fibrosis in rats fed alcohol and a high fat—low
protein diet. Am. J. Pathol. 132:73–85.
Friedman, S. L. 1999. Stellate cell activation in alcoholic fibrosis-an overview.
Alcohol. Clin. Exp. Res. 23:904–910.
Galis, Z. S., Asanuma, K., Godin, D., and Meng, X. 1998. N-acetyl-
cysteine decreases the matrix degrading capacity of macrophage derived
foam cells. New target for antioxidant therapy? Circulation 97:2445–
2453.
Gouillon, Z., Lucas, D., Li, J., Hagbjork, A. L., Freuch, B. A., Fu, P., and Fang,
C. 2000. Inhibition of ethanol induced liver disease in the intragastric feeding
rat model by chlormethiazole. Proc. Soc. Exp. Biol. Med. 224:302–308.Herrera, J. J. O., Huertas J. R., Queles, J. L., and Mataix, J. 2001. J. Nutr. Chem.
12:357–364.
Isao, O., Tetsu, W., Shigenari, H., Niioka, M., Masao, A., and Maruyama, K.
2001. Reversibility of hepatic fibrosis: from the first report of collagenase in
the liver to the possibility of gene therapy for recovery. Keio. J. Med. 50:58–
65.
Jaya, D. S, Augustine, J., and Menon, V. P. 1994. Protective role of
N-Acetyl-L-cysteine against alcohol and paracetamol induced toxicity. Ind.
J. Clin. Biochem. 9:64–71.
Jethmalani, S. M., Viswanathan, G., Bandyopadhyay, C., Noronha, J. M. 1998.
Effectsof ingestion ofthermally oxidizededibleoils onplasma lipids,lipopro-
teins and postheparin lipolytic activity of rats. Ind. J. Exp. Biol. 27:1052–
1055.
Lichtinghagen, R., Michels, D., and Haberkorn, C. I. 2001. Matrix metallopro-
teinases (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 arerelated to the fibroproliferative process in the liver during chronic hepatitis C.
Hepatol. 34:239–247.
Lichtinghagen, R., Steinmetz, C., Pehle, B., Seifert, T., Breitenstein, K., and
Boker, K. H. W. 1999. Matrix metalloproteinases in liver and serum in
chronicactivehepatitis C andHCV – inducedcirrhosis. Hepatol.Res. 14:119–
134.
Lieber, C. S. 1993. Biochemical factors in alcoholic liver disease. Semin. Liv.
Dis. 13:136–153.
Lieber, C. S. 2000, Alcoholic liver disease: new insights in pathogenesis lead to
new treatments. J. Hepatol. 32:113–128.
Mehde, M., Grundamann, A., Saile, B., Scharf, J. G., and Ramadori, G. 1997.
Expression of matrix metalloproteinases and their inhibitors during hepatic
tissue repair in rats. J. Hepatol. 26:574–584.
Mignatti, P., and Rifkin, D. B. 1993. Biology and biochemistry of proteinases
in tumor invasion. Physiol. Rev. 73:161–195.
Moshage, H., Casini. A., and Lieber, C. S. 1990. Acetaldehyde selectively stim-
ulates collagen production in cultured rat liver fat storing cells but not in
hepatocytes. Hepatol. 12:511–518.
Nangi, A. A., Zhao, S., Sadzadeh, S. M. H., Dannenberg, A. J., Tahan S. R., and
Waxman, D. J. 1994. Markedlyenhancedcytochrome P4502E1 induction and
lipid peroxidation is associated with severe liver injury in fish oil-ethanol fed
rat. Alcohol. Clin Exp. Res. 18:1280–1285.
Niemala, O., Parkkila, S., Herttula, Y. S., Villanueva, J., Ruebner, B., and Hal-
sted, C. H. 1995. Sequential acetaldehyde production, lipid peroxidation and
fibrogenesis in micropig model of alcohol induced liver disease. Hepatol.
22:1208–1214.
Overall, C. M., Wrana, J. L., and Sodek J. 1991. Transcriptional and post
transcriptional regulation of 72-kDa gelatinase/type IV collagenase by trans-
forming growth factor β1 in human fibroblasts. J. Biol. Chem. 226:14064–
14071.
Preaux, A. M, Mallat, A., Nhieu, J. T., D’Ortho, M. P., Hemburg, R. M.,and Mavier, P. 1999. Matrix metalloproteinase-2 activation in human
hepatic fibrosis regulation by cell matrix interactions. Hepatol. 30:944–
950.
Rajagopalan, S., Meng, Y. P., Ramasamy, S., Harrison, D. G., and Galis, Z. G.
1996. Reactive oxygen species produced by macrophage-derived foam cells
regulate the activity of vascular matrix metalloproteinases in vitro: Implica-
tions for atherosclerotic plaque stability. J. Clin. Invest. 98:2572–2579.
Rajakrishnan, V., Viswanathan, P., and Menon, V. P. 1997. Adaptation of sib-
lings of female rats given ethanol effect of N-acetyl-L-cysteine. Aminoacids
12:323–341.
8/8/2019 Changes in activities of MMP in alcohol and thermally oxidized sunflower oil induced liver damage: NAC antioxidant…
http://slidepdf.com/reader/full/changes-in-activities-of-mmp-in-alcohol-and-thermally-oxidized-sunflower-oil 9/9
274 S. V. PENUMATHSA ET AL.
Rajakrisnan, V., Viswanathan, P., and Menon, V. P. 1997. Hepatotoxic effect of
alcohol on female rats and siblings: effects of N-acetylcysteine. Hepatol.Res.
9:37–50.
Rukkumani, R., SriBalasubashini, M., Viswanathan, P., and Menon, V. P. 2002.
Comparative effects of curcumin and photo irradiated curcumin on alcohol
and polyunsaturated fatty acid—induced hyperlipidemia. Pharmacol. Res.
46:257–264.
Tuma, D. J, Thiele, G. M., Xu, D, Klassen, L. W., and Sorrel, M. F., 1996.
Acetaldehyde and malondialdehyde reacttogetherto generate distinctprotein
adductsin theliverduringlong-termethanoladministration. Hepatol.23:872–
880.
Twefix, H.,Ismail,H. M, andSumars, S. 1998. Theeffect of intermittent heating
on some chemical parameter of refined oils used in Egypt: A public health
nutrition concern. Int. J. Food Sci. Nutr. 49:339–342.
Yin, M., Wheeler, M. D., Kono, H., Bradford, B. U., Gallucci, R. M., Lus-
ter, M. I., and Thurman, R. G. 1994. Essential role of tumor necrosis fac-
tor alpha in alcohol induced liver injury in mice. Gastroenterol. 117:942–
952.