Silybum marianum as a hepatoprotective agent


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Silybum marianum as a hepatoprotective agent

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  2. 2. Introduction: The liver is one of the largest and most important organs in the human body. It islocated behind the lower right section of the ribs. The liver performs a wide range ofmetabolic activities required for homeostasis, nutrition and immune defense. Forexample, it is important in the removal and breakdown of toxic materials from theblood and the regulation of blood glucose and lipids, the storage of certain vitamins,iron, and other micronutrients, and in breaking down or modifying amino acids. It isinvolved in a plethora of other biochemical reactions1.The liver is the central organ for detoxification and clearance of exogenous andendogenous substances, constitutes a primary target for toxic reactions, the major liverdiseases are hepatitis, cirrhosis, and dysfunctions related to bile secretion. Hepatitis ischaracterized as an inflammation of the liver that can be present with or withoutcirrhosis. Many different drugs can cause drug-induced hepatitis. Painkillers and feverreducers that contain acetaminophen are a common cause of liver inflammation.Forms of viral hepatitis include hepatitis A, B, and C. Cirrhosis is a state in which thetissue in the liver breaks down, becoming fatty and fibrous which can lead to liverfailure. According to NWHIC (National Womens Health Information Center ) morethan 60,000 Americans die each year due to liver failure, Global prevalence of chronichepatitis C is estimated to average 3%. There are some 175 million chronic HCVcarriers throughout the world, of which 2 million are in the USA and 5 million inWestern Europe. HCV accounts for 20% of cases of acute hepatitis, 70% of cases ofchronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepato-cellular carcinoma and 30% of liver transplants. Incidence of new symptomaticinfections has been estimated to be 1–3 per 100 000 persons annually 2. According to(NCHS, CDC) there are 27,035 deaths from alcohol related chronic liver disease andcirrhosis each year in the US (Deaths: Final Data for 2001, NCHC, CDC). Botanicals have been used traditionally by herbalists and indigenous healersworldwide for the prevention and treatment of liver diseases. Clinical research in thisCentury has confirmed the efficacy of several plants in the treatment of liver diseases.Silybum marianum (milk thistle) is one of the medicinal plants that has been shown tohave clinical applications in the treatment of toxic conditions of the liver12. Silymarinmay be used in many cases of liver diseases and injury, including hepatitis, cirrhosis,and jaundice. Helps repair liver cells damaged by alcohol and other toxic substances.Silymarin has been shown to protect animal livers against the damaging effects ofcarbon tetrachloride, alcohol, drugs such as paracetamol, and the toxins α-amanitinand phalloidin found in the death cap fungus (Amanita phalloides). Silymarin alsokeeps new liver cells from being destroyed by these same substances, reduces hepaticinflammation and has potent antioxidant effects11. 2
  3. 3. History: Silybum is cited as one of the oldest known herbal medicines. Dioscorides firstdescribed the plant. In Roman times, Pliny the Elder (A.D. 77), a noted naturalist,described the medicinal uses of milk thistle, indicating it was “excellent for carryingoff bile.” Culpeper (1650) wrote of its effectiveness in removing obstructions of theliver and spleen12.Botany: Silybum marianum is currently the most well researched plant in the treatmentof liver diseases.The genus Silybum is a member of Compositae family (Asteraceae).The plant itself is a stout thistle, growing one to three meters tall in rocky soils, withlarge purple flowering heads (Figure below). The leaves are characterized by distinctwhite “milky” veins that give the plant its common name (milk thistle)14. The activeconstituents of milk thistle are flavonolignans including silybins, isosilybins,silydianin, and silychristine, collectively known as silymarin.Silybin and isosilybinhave two isomers. Silybin is the component with the greatest degree of biologicalactivity11. Silymarin is found in the entire plant but is concentrated in the fruit andseeds. Silybum seeds also contain 20–30% essential fatty acids such as Linoleic acid,oleic acid and palmitic acid9.Silybum marianumKingdom: PlantaePhylum: MagnoliophytaClass: MagnoliopsidaOrder: AsteralesFamily: AsteraceaeGenus: SilybumSpecies: marianum 3
  4. 4. Chemistry:Chemical constituents9:Physicochemical properties: The anhydrous silybin has mp 158°C and it decomposes at 180°C. Its physicalcharacteristics are as follows: Its UVmax (in methanol): 288 nm. It is soluble inacetone, ethyl acetate, methanol, and ethanol and found to be sparingly soluble inchloroform. It is practically insoluble in water16.Extraction of flavonolignans The typical silymarin extraction process involves the defatting of the seeds in aSoxhlet extraction with petroleum ether for 4 hours followed by a second Soxhletextraction with methanol for 5 hours18. 4
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  6. 6. Pathophysiology: Liver is a major detoxifying organ in the body, so it’s under a high risk oftoxicity; some causes include drugs, chemicals, free radicals, radiation, metals. freeradicals cause peroxidation of cell membrane lipids of hepatocytes which containunsaturated lipids such as phospholipids, this will lead to a free radical chain reactionand damage the cell membrane, severe exposure to free radicals may cause cancerbecause these free radicals may cause peroxidation of nuclear membrane ofhepatocytes and attack the DNA and make mutations in the sequence of DNA2,5 .Destruction of hepatocytes will lead to exposure of its content to the interstitial fluidand this is characterized by a buildup of liver enzymes in the blood, these enzymesinclude aspartate aminotransferase (AST),alanine aminotransferase (ALT) andalkaline phosphatase 3.When liver function tests are assesed , four general patterns are apparent: 1. acute hepatitis pattern, which has elevated transaminase levels and variable increases in other enzymes 2. cirrhosis pattern, which has decreased albumin, elevated gamma globulins. 3. chronic hepatitis pattern, which has a combination of changes seen in acute hepatitis and cirrhosis patterns 4. obstructive liver disease pattern, also called cholestasis, which has an elevated ALP and bilirubin19. One of the major causes of liver diseases and toxicities is ethanol, metabolismof ethanol produces acetaldehyde, acetaldehyde promotes GSH depletion,it has alsobeen shown to stimulate collagen synthesis by liver stellate cells, which might beinvolved in the pathogenesis of ethanol-induced liver cirrhosis. ethanol oxidation notonly reduces gluconeogenesis but also accelerates triglyceride synthesis from freefatty acids, which leads to an accumulation of fat in the liver parenchyma5. mushroom poisoning by Amanita phalloides, Amanita mushrooms possess twoextremely powerful hepatotoxins, amanitin and phalloidin, Amatoxin poisoningproduces massive hepatic necrosis, Once inside the cell, α – amanitin inhibittranscription of DNA, resulting in the inhibition of protein synthesis and cellnecrosis5. Hepatocytes contain certain residues called Glutathione which neutralizes freeradicals, the ability of glutathione decreases in alcoholic persons as it suppresses thefunction of glutathione and they become more susceptible to toxicity 4,5. 6
  7. 7. Pharmacology:Pharmacokinetics: Silymarin is not water soluble so it cannot be taken as a tea.The absorption withoral administration is rather low with only 2%-3% of the silybin recovered in 24hours from rat bile. The peak plasma levels after an oral dose are achieved in 4-6hours in both human and animals. Silymarin is cleared from the body predominantlyvia bile and to a lesser extent the kidneys. The half-life of silymarin is 6-8 hours12.Silymarin is complexed with phospholipids like phosphatidylcholine give rise to anew drug delivery technology called phytosome showing much better absorptionprofile following oral administration owing to improved lipid solubility which enablesthem to cross the biological membrane, resulting enhanced bioavailability i.e. moreamount of active principle in the systemic circulation20,also SMEDDS(self-microemulsifying drug delivery system) could be use to improove solubility ofsilymarin,The basic principle of this system is spontaneous formation of an emulsionin the gastrointestinal tract that presents the drug in a solubilized form21.Pharmacodynamics:Mechanisms of action22 The flavonolignans of Silybum marianum have hepatoprotctive activity, theirmechanisms of action include 1. As antioxidants, free radical scavengers and regulators of the intracellular content of glutathione. 2. as cell membrane stabilizers and permeability regulators that prevent hepatotoxic agents from entering hepatocytes; 3. As promoters of ribosomal RNA synthesis, stimulating liver regeneration. 4. as inhibitors of the transformation of stellate hepatocytes into myofibroblasts.Antioxidant activity Silymarin and silibinin (silybin) are antioxidants that react with free radicalstransforming them into more stable and less reactive compounds. Silymarin andsilybin have been reported to inihibit lipid peroxidation. In rats, intraperitonealsilymarin has been shown to increase total glutathione in the liver, intestine andstomach and to improve the reduced glutathione to oxidised glutathione ratio9.Stimulation of liver regeneration: One of the mechanisms to explain the ability of silymarin to stimulate theregeneration of hepatic tissue is the increase in protein synthesis in damaged livers.ithas been demonstrated that Silybin binds to a regulative subunit of RNA-polymeraseand activates this enzyme; as a consequence the synthetic rate of ribosomal RNA isenhanced leading to an increased formation of intact ribosomes which result inincreased protein synthesis6. 7
  8. 8. Membrane stabilizing activity: In case of mushroom poisoning silymarin is able to protect liver from damagingeffects of this mushroom because silymarin stabilizes the cell membrane ofhepatocytes ,thus inhibit entry of the toxins22.Antifibrotic effects: Silybin was found to reduce the proliferation of freshly isolated rat hepaticstellate cells by about 75 percent. It also reduced the conversion of stellate cells intomyofibroblasts.Anti-inflammatory effects: Silymarin has been shown to have significant anti-inflammatory effects onhepatic tissue by inhibition of neutrophil migration, inhibition of Kupffer cells,marked inhibition of leukotriene synthesis and formation of prostaglandins, theinhibitory effect on 5-lipoxygenase pathway resulting in inhibition of leukotrienesynthesis12.Inhibition of cytochrome P450: silymarin has an inhibitory effect on the cytochrome P450 (Phase I)detoxification system, it will inhibit p450 reversibly. silymarin and otherantioxidants afford some protection against the free radicals generated by P450enzymes10.Dosing: The typical dose for silymarin is 240-900 mg/day in two or three divided doses. 15.Toxicity: Even in large doses silymarin is devoid of toxic effects and in particular has noharmful action on the embryo. In isolated cases, a mild laxative effect has beenobserved15. Two separate clinical trials of milk thistle in pregnant women yieldedpositive results with no evidence of harmful effects on the pregnancy8.Conclusion:*Silybum marianum is an important plant for protection of an important organ, whichis liver* It is a very familiar plant ,very cheap ,can easily be achieved even by non practicedpersons, and be used to its important purposes.and we should know that kurdistan isrich with this plant so we should take in mind that it can be used for this purpose in ascientific way. 8
  9. 9. References: 1. Susan Standring, (2008).Grays Anatomy the Anatomical Basis of Clinical Practice, 40th edition, Elsevier. 2. Sherlock S, Dooley J., (2002).Diseases of the Liver and Biliary System, 11th edition.P 305, Blackwell. 3. Marilyn Barrett, (2004).The Handbook of Clinically Tested Herbal Remedies volume 1,p 933-936, Haworth Press. 4. McPhee, Ganong, William F.,Stephen J.,(2006) Pathophysiology of Disease: An Introduction to Clinical Medicine, 5th edition. McGraw-Hill. 5. Frank A. Barile, (2005). Clinical toxicology: principles and mechanisms, 266CRC Press. 6. James E.Robbers,Marilyn K.Speedie,Varro E. Tyler,(1996).Pharmacognosy and pharmacobiotechnology.First Edition,Williams and Wilkins a Waverly company. 7. Vinay Kumar, Abul K. Abbas, Nelson Fausto, Richard Mitchell, (2007). Robbins Basic Pathology.8th Edition, Elsevier. 8. Aviva Romm, (2010). Botanical medicine for women’s health,p 591, Elsevier. 9. Joanne Barnes, Linda A. Anderson, J David Phillipson,(2007).Herbal Medicines.Third edition,p 429-434, Pharmaceutical Press. 10. Lasley Braun,Marc Cohen,(2007). Herbs and natural supplements.second edition,p 1039- 1049,Elsevier. 11. Dewick P. M., (2009). Medicinal natural products a biosynthetic approach.third edition, p 174-176,John Wiley & Sons. 12. S. Luper, (1998).A review of plants used in the treatment of liver diseases: Part 1, Altren Med Rev 3: 410-421. 13. 14. Lidia Radko, Wojciech Cybulski, (2007). Application of sylimarin in human and animal medicine. Journal of Pre-Clinical and Clinical Research, Vol 1, No 1, 022-026. 15. Ikhlas A. Khan, Ehab A. Abourashed, (2010). Leungs Encyclopedia of Common Natural Ingredients: Used in Food, Drugs and Cosmetics. Third Edition,p 439-442, John Wiley & Sons. 16. Ashutosh Kar, (2007).Pharmacognosy and pharmacobiotechnology.Second Edition,p 365,new age international publishers. 17. WHO monographs on selected medicinal plants. Volume2. World health Organisation Geneva, 2002, p 306-307. 18. Donald G. Barceloux,( 2008).Medical toxicology of natural substances, p 553-557, John Wiley & Sons. 19. Walter L. Kemp, Dennis K. Burns, Travis G. Brown,(2008).The big picture pathology,p 261-262, McGraw-Hil. 20. Sindhumol P. G., Maria Thomas, Mohanachandran P. S.,(2010), phytosomes: a novel dosage form for enhancement of bioavailability of botanicals and neutraceuticals, international journal of pharmacy and pharmaceutical sciences, Vol 2, Issue 4, 2010, ISSN- 0975-1491. 21. 2.Xin-Ru Li, Yu-Sheng Pei, Yan-Qing Huang, Yan-Xia Zhou, Yu-Chen Zhang, Yan Liu,( 2009). In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for silybin. Journal of Chinese Pharmaceutical Sciences. 4: 342-347, 1003-1057. 22. Fraschini F, Demartini G, Esposti D., (2002). Pharmacology of silymarin. Clin Drug Invest., 22 (1), 51-65. 9