Role of Flavanoids in Free Radical Induced Hepatic Fibrosis

 

*Merlin NJ, V Parthasarathy and R Manavalan

Department of Pharmacy, Annamalai University, Annamalai Nagar, 608002 Tamil Nadu  India

*Corresponding Author E-mail: merlinbinu76@yahoo.co.in

 

ABSTRACT

The liver is remarkably a complex organ with array of functions that have effect on nearly every other systems of the body.  Molecular oxygen is an essential component of all living organisms, but higher oxidative stress leads to generation of free radicals in the process.  There is accumulating evidence that these free radicals play a considerable role in the development of hepatic fibrosis by acting in different cell types and in different signaling pathways.  Consequently, flavanoids, a group of phenolic compounds found naturally in fruits, vegetables, nuts, flowers, seeds and barks    which are of plant origin ,have emerged as potent antifibrotic agents. Its main role as antifibrotic activity is due to its free radical scavenging activity. This review briefly summarises current views of the mechanisms of fibrogenesis and recent findings on the antihepatofibrotic potential of flavanoids

 

KEY WORDS:    Free radicals,  Flavanoids, Hepatic Fibrosis, Anti oxidant activity.

 


INTRODUCTION:

Free radicals are reactive molecules involved in many physiological processes and human diseases such as cancer, aging, arthritis, Parkinsons syndrome,ischaemia and hepatic injury . Compounds that can scavenge free radicals have great potential in ameliorating these disease process1.  These free radicals attacks unsaturated fattyacids of biomembranes  and results in lipid peroxidation and destruction of proteins and DNA2,3.  The elevation of free radical levels seen during the hepatic damage is owing to enhanced production of free radicals and decreased scavenging potential of the cells. Antioxidants plays an important role to protect human body against damaging reactive oxygen species4. A variety of intrinsic antioxidants (reduced glutathione, superoxide dismutase (SOD), catalalase and peroxidase)are present in the organism which protect the body from free radicals thereby forming the first line of defence5.

 

In addition to the intrinsic antioxidants,plant derived flavanoids have potent hydroxyl free radical scavenging property.Hydroxyl radical(·OH) generated by the Fenton reaction cause oxidatively induced DNA strand breakage and yields open circular DNA (relaxed circular DNA).  Hydroxyl radical scavengers protect DNA from strand  breaks induced by hydroxyl radical6.

 

Hepatic fibrosis and cirrhosis developing in response to chronic hepatocellular injury are characterized by specific cellular reactions that are orchestrated by a set of cytokines and other signaling molecules and finally lead to excessive deposition of extracellular matrix proteins7.  As these processes continue, remodeling of liver architecture is apparent and results in severe pathophysiological consequences like liver insufficiency, portal hypertension and hepatic encephalopathy.  Although hepatic fibrosis is of high incidence worldwide, the management of these diseases is still insufficiently worked out.  Recent program in the understanding of pathological mechanism may open new strategies with which to interface at early steps in the development of disease.

 

FREE RADICALS.

Free radicals are chemical species with single unpaired electron in an outer orbit.  Such chemical states are extremely unstable and readily react with inorganic or organic chemicals8.  When generated in cells they attack and degrade nucleic acids and a variety of membrane molecules.  In addition free radicals initiate autocatalytic reactions, that is molecules that react with free radicals are in turn converted into free radicals, further propagating the chain of damage.

 

FREE RADICAL GENERATION:

Free radicals are generated by enzymatic and nonenzymatic reactions from oxygen as follows. 

 

1. Superoxide (O2·):

Superoxide anion O2· is generated by direct auto oxidation of oxygen during mitochondrial electron transport chain.  Alternatively O2· is produced enzymatically by xanthine oxidase and cytochrome  P450 in the mitochondria or cytosol. O2· so formed is catalolised to produce H2O2 by superoxide dismutase (SOD).

 

2. Hydroxyl radical (OH-):

OH- radical is formed by 2 ways. 

(i) by radiolysis of H2O and  (ii) by reaction of H2O2 with Ferrous (Fe++) ions.

 

This reaction is termed Fenton reaction. Fig1shows schematic representation of mechanisms of generation of free radicals by free radicals. 

 

The reactive oxygen species (ROS), such as Superoxide anion radical (O2-) hydrogen peroxide, (H2O2), and hydroxyl radical (OH·),have been implicated in the pathophysiology of various clinical disorders, including ischaemia, reperfusion injury ,atherosclerosis ,acute hypertention, diabetes mellitus and cancer.

 

Free radical reactions

The hydroxyl radical is the most reactive species. It may produce membrane damage by following mechanisms

 

1.Lipid peroxidation:

Polyunsaturated fatty acids (PUFA)of membrane are attacked repeatedly by oxygen derived free radicals to yield highly destructive PUFA radicals –lipid hydroperoxy  radicals and lipid hydroperoxides. This reaction is termed lipid peroxidation.  Lipid peroxidation cause membrane damage and destruction of organelles.

 

2. Oxidation of proteins:

Oxygen derived free radicals causes cell injury by oxidation of protein macromolecules of the cell and results in degradation of cytosolic neutral proteases and cell destruction.

 

3. DNA damage:

Free radicals cause breaks in single strands of nuclear and mitochondrial DNA .This results in cell injury.  It may also cause malignant transformation of cells.

 

4.Cytoskeletal damage:

Reactive oxygen species interact with cytoskeletal elements and interferes with mitochondrial phosphorylation and cause ATP depletion.Fig.2 shows the mechanism of cell death by hydroxyl radical, the most reactive oxygen species.

 

FLAVANOIDS

Flavanoids are a group of phenolic compounds found naturally in fruits, vegetables, nuts, flowers, seeds, and barks and are derived from a C6-C3 (polypropane) unit

 

 

which has as its source shikimic acid (via phenyl alanine) and a C6 unit derived from polyketide pathway.  This polyketide fragment is generated by three molecules of malonyl CoA ‘which combines with the C6-C3 unit to form a triketide starter unit. Fig.3 represents the steps involved in formation of a flavone.

 

Flavanoids are therefore of mixed biosynthesis, consisting of units derived from both shikimic acid and polyketide pathmays9.


 

Mojzisova and  Kuchta10 have reported that  flavanoids exhibit a wide range of biological effects including anti-inflammatory ,antiallergic ,antiviral ,anti carcinogenic, anti ischaemic ,antiplatelet, antilipoperoxidant and gastroprotective actions. Furthermore flavanoids are potent antioxidants ,free radical scavengers and metal chelators and inhibits lipid peroxidation. Most of the flavanoids are potent inhibitors of several enzymes like xanthine oxidase, cyclooxygenase, and lipo oxygenase11, 12. A major property of flavanoids is their ability to scavenge hydroxyl radicals. Isovitexin, a glycosyl flavanoid was found to be the most effective.This antioxidant activity of isovitexin is comparable to those of α-tocopherol and ascorbic acid13.

 

Flavanoids have important dietary significance, because .being phenolic compounds they are strongly antioxidant in action.

 

Many disease states are known to be exacerbated by the presense of  superoxide and hydroxyl free radicals and flavanoids have the ability to scavenge and effectively ‘mop up’ these damaging oxidizing species.Foods rich in this group has important role in ameliorating diseases such as cancer and heart disease  (which can be worsened by oxidation of low –density lipoprotein)

       

Stilbenes sometimes referred to as biphenyls or stilbenoids are related to flavanoids and have basic structure C6-C2-C6.Fig.4 is the structure of a stilbene.  Stilbene arises from the loss of one carbon (as CO2) from the triketide starter unit.  The simplest member of this class is stilbene.One of the important compound of this class is resveratrol,a component of red wine and it has antioxidant ,anti cancer and anti inflammatory activities.  There is low incidence of

 

heart disease among the French population where large concentrations of fatty acids are present in the diet. This low rate of heart disease is due to consumption of red wine ,which is rich in resveratrol and other flavanoids.

 

THE LIVER

The liver is the principal site of synthesis of all circulating proteins. The liver also synthesizes all factors involved in coagulation. Glucose homoeostasis and the maintenance of the blood sugar is a major function of the liver. The liver also has a major role in the metabolism of lipoproteins.  This catabolises hormone such as insulin, glucagons, oestrogens, growth hormone, glucocorticoids and parathyroid hormone. It is the major site for the metabolism of drugs and alcohol.  The reticuloendotheial system of the liver contains many immunologically active cells .The liver acts as a sieve for the bacterial and other antigens carried to it via the portal tract from the gastrointestinal tract.  The antigens are phagocytosed and degraded by Kupffer cells, which are macrophages attached to the endothelium14-19. The liver regulates the conversion of toxic ammonia to less toxic urea for filtration and excretion by the kidneys20-21. The liver performs all the process of secretion, regulation and storage via the use of specific genes for operation that are located on the chromosomes inside the nucleus of the hepatocytes22-26.

 

HEPATIC FIBROSIS

The liver is composed of six major cell types; hepatocytes, bile duct epithelial cells (collaginocytes), kupffer cells, hepatic stellate cells, and sinusoidal epithelium and pit cells. In addition arterial and venous structures are lined by vascular endothelium and contain vascular smooth cells.Each of the major cell type plays a significant role in liver, during injury27. Hepatocytes when injured may produce and release oxygen free radicals, lipid peroxide products, proteases, cytokines and growth factors that injure adjacent cells.  Injury may activate Kupffer cells and  hepatic macrophages resulting in increased phagocytosis and elaborates a large number of secretory products including Tumour necrosis factor, Interferon alpha-1and beta-1, Interleukin(IL)-1, (IL)-6, Prostaglandin-2, leukotrienes, superoxide, proteases,nitric oxide and many other proinflammatory compounds. This results in activation of T cells, cytotoxicity, magnification of inflammatory responses and stimulation of fibrogenesis.

 

Fibrosis and Cirrhosis

The harmful outcome of chronic inflammation is fibrosis. It is seen as scar formation in patients liver. The scar occurs when the liver tries to repair damaged tissue28. Liver fibrosis results from excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury29.

 

Cirrhosis is the result of continuous liver damage through chronic inflammation and the development of fibrotic areas throughout the liver. Cirrhosis leads to reduction of blood supply to liver. The causes of cirrhosis includes viral hepatitis ,excessive intake of alcohol ,inherited diseases and haemochromatosis.

 

Nature and origin of Hepatic Fibrosis

Activated Hepatic Stellate Cells (HSC) are major producers of fibrotic neomatrix. Hepatic stellate cells in normal liver are major storage sites of Vitamin-A,which is stored in cytoplasm as retinyl esters. Follwing a chronic liver injury ,HSC proliferates ,lose their Vitamin A and undergo phenotypical transformation to smooth muscle actin positive myofibroblasts(activated HSC) which produces a wide variety of collaginous ECM proteins30.  Stellate cell activation in response to liver injury is a two stage process beginning with initiation, which renders the cell responsive to a host cytokines and stimuli ,producing changes in Extracellular Matrix ( ECM ) composition.

 

In liver injury there is increased deposition of collgen type I and IV, undulin, elastin and laminin. Hyaluranan, dermatan, chondroitan sulphate and heparin sulphate proteoglycans are also increased. Complete recovery of liver fibrosis involve remodeling and breakdown of ECM components, with degradation of predominant component collagen I and III with the help of enzymes.

 

Resolution of Liver Fibrosis

During recovery from acute human liver injury, the number of activated stellate cells decreases as the tissue integrity is restored. Two possibilities are reversion of stellate cells activation or stellate clearance of activated stellate cells by apoptosis.

 

1. Reversion:

The plating of highly activated cells in the basement membrane of substratum down regulates stellate cell division.

 

2. Apoptosis:

Apoptosis is the default mode of activated hepatic stellate cells in normal liver.Thus following an injury apoptosis is inhibited by soluble factors and matrix components that are present during injury.

 

Induction of hepatic fibrosis

For in vivo animal studies the most widely used method for inducing Hepatic Fibrosis is administration of carbon tetra chloride (CCl4).  This CCl4 undergoes bioactivation by cytochrome P450 to a reactive metabolite trichloro methyl radical.  The free radical thus generated causes hepatic injury by initiating lipid peroxidation.  Following this there will be scar formation in the liver cells due to proliferation of Hepatic stellate (HSC) and excessive deposition of Extracellular Matrix (ECM).  There will be elevation of enzyme levels like aspartate amino transferase(AST),alanine aminotransferase (ALT )and alkaline phosphatase

(ALP) following CCl4 administration and this indicates hepatic injury and fibrosis.  This is further substantiated by the increase in the liver weight, which might be due to deposition of collagen. Similarly hepatotoxicity can be induced by ethanol, paracetamol31, lead32, antitubercular drugs33.

 

Anti fibrotic efficiency –in vitro studies

Even though the efficacy of antifibrotic agents can be demonstrated by in vivo studies, mechanistic details of this can be derived from in vitro studies. The tuber mucilage extracted and purified from Dioscorea batatas exhibited antioxidant activities in a series of tests i.e 1,1-diphenyl -2-picryl hydrazyl (DPPH) radical scavenging activity assays,reducing power test, anti –lipid peroxidation and anti human low density lipoprotein perooxidation tests and are comparable  with butylated hydroxytoluene(BHT) ,reduced glutathione or ascorbic acid.Their result suggest that it plays main role as antiradical and antioxidants34

 

The in vitro antioxidant activity of  the ethanolic  extracts  of  the roots and rhizomes of Cyperus rotundus Linn. was evaluated by estimating the degree of  non –enzymatic haemoglobin glycosylation ,measured colorimetrically at 520 nm . The preliminary phytochemical screening confirmed the presence of flavanoids which is mainly responsible for the activity35.

 

Anti fibrotic efficiency –in vivo studies

There are many evidences for the effectiveness of plant derived antioxidants against hepatic fibrosis.Silymarin ,the active principle from Carduus marianus L .is proved to be antifibrogenic in humans36,37 and in rat fibrosis model38,39 where it led to a reduction of hepatic collagen accumulation by more than 35% .It is well known that silymarin and its component silibinin have potent antioxidant activity40,41  In an ethanol induced peroxidative damage model  the plant Trigonella Foenum Graceum Linn was found to have potent antifibrotic efficiency which is due to its antioxidant activity42 .This was confirmed by estimating the malondialdehyde content of the rat brain, which is one of the products of lipid peroxidation.The inhibition of lipid peroxidation  level was  comparable to that of vitamin E which is used as standard43

 

Therapeutic potential of plant Derived Flavanoids in Liver Fibrosis.

Fruits and vegetables provides protection against diseases including cancer, hepatic fibrosis, cardiovascular and cerebrovascular diseases, that has been attributed to the various anti oxidants contained in them.  Fruits and vegetables contain many different antioxidant components.  Majority of their antioxidant capacity may be from compounds other than vitamin C, vitamin E or β– carotene.  For example some flavanoids (including isoflawanes, flavonones, anthocyanins, catechins and isocatechins) are frequent components of the human diet and have strong antioxidant activities as reported by Hanasaki etal44.  The beneficial health effects attributed to the consumption of fruits and flavanoids are related to their antioxidant activity.  Citrus fruits have high free radical scavenging ability because of its antioxidant potency, so it is generally protects, lipids and DNA, which is an integral part of the body’s defence mechanisms45.

              

For a long time, the therapeutic potential of flavanoids with respect to fibrosis was realised only marginally46, 47, 48, 49.  In the last few years a number of studies has dramatically changed this situation50 placing free radical injury and the antifibrotic potential of flavanoids into focus.  Following treatment with flavanoids all the elevated enzyme levels will get reduced and also the weight of the liver reverts to normal.  The reason for reverting the fibrotic potential of liver to normal by flavanoids is mainly due to its antioxidant activity which has main role as free radical scavangers.  Even traditional drugs like pentoxifylline51 as well as known phosphodiesterase inhibitor, were unexpectedly found to block perisinusoidal stellate cells activation by interfering with the oxidative stress cascade suggesting new mechanisms for their anti fibrotic activity.

 

Flavanoids show a remarkable potency to block fibrogenesis of different etiology.  Since the few examples studied so far have just opened a wide horizon, it is worth to screen other plant extracts and natural compounds in appropriate model systems and to look for further compounds combining free radical scavenging properties with other effector functions.  Such studies may lead to new drugs particularly suited and specifically tailored to block liver fibrosis at early steps of pathogenesis.  On the basis of preliminary experimental results, it may be expected that such drugs are suitable also for preventive care and for supporting the endogenous regenerating capacity of the liver, once fibrosis has already developed.

 

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Received on 17.11.2008           Modified on 24.12.2008

Accepted on 12.02.2009          © RJPT All right reserved

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 52-57