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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



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).



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.




FIG. 3. Densitometry of Liver Multiwell Zymogram.

FIG. 4. Changes in the activities of Matrix Metalloproteinases in liver.




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




FIG. 7. Densitometry of liver zymogram.

FIG. 8. Changes in the activities of MMP-2.

FIG. 9. Changes in the activities of MMP-9.




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.

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