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Hepatoprotective effects of milk thistle seed (Silybum marianum)

  • Malatya Turgut Özal University


Milk thistle has been used for centuries to treat acute and chronic liver diseases and, even today, is one of the most widely used herbal medications. Its primary active ingredient is silymarin, which is a potent antioxidant composed of several flavonoid compounds (which includes silybin [silibinin], silidianin, silychristin [silichristin] and isosylibin). The dried seeds contain 1-4% silymarin flavonoids. The aim of this article with the theme hepatoprotective effects of Milk thistle seed and the possibility of inhibition of the endogenic cholesterol synthesis in the liver by silymarin are shown.
Hepatoprotective Effects Of Milk Thistle Seed (Silybum Marianum)
Milk thistle has been used for centuries to treat acute and chronic liver diseases and,
even today, is one of the most widely used herbal medications. Its primary active ingredient is
silymarin, which is a potent antioxidant composed of several flavonoid compounds (which
includes silybin [silibinin], silidianin, silychristin [silichristin] and isosylibin). The dried seeds
contain 1-4% silymarin flavonoids. The aim of this article with the theme hepatoprotective
effects of Milk thistle seed and the possibility of inhibition of the endogenic cholesterol
synthesis in the liver by silymarin are shown.
Keywords: Behavior and Behavior Mechanisms, Liver, Milk thistle,
Milk Thistle (Silybum marianum) is a mediterranean plant that has been used to treat
liver ailments. Silybum marianum (milk thistle) has been shown to have clinical applications
in the treatment of toxic hepatitis, fatty liver, cirrhosis, ischemic injury, radiation toxicity, and
viral hepatitis.1 Silymarin presents a pharmacologically effective substance containing four
main constituents: silybin (50 60%), isosilybin (5%), silychristin (20%) and silydianin
(10%).2 Silymarin is a derivative from the milk thistle plant with few side effects that has
been safely used for centuries to treat liver ailments.3 Silymarin consists of four
flavonolignan isomers namely–silybin, isosilybin, silydianin and silychristin. Among them,
silybin being the most active and commonly used. Other flavonolignans identified in S.
Maria-num include dehydrosilybin, deoxysily-cistin, deoxysilydianin, silandrin, silybi-nome,
silyhermin and neosilyhermin.In addition, milk thistle contains apigenin; silybonol; myristic,
oliec, palmitic and stearic acids; and betaine hydrochloride, which may have a
hepatoprotective effect.4 Silymarin is orally absorbed and is excreted mainly through bile as
sulphates and conjugates. Silymarin offers good protection in various toxic models of
experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid
peroxidative, antifibrotic, anti-inflammatory, memb-rane stabilizing, immunomodulatory and
liver regenerating mechanisms.5 The German Commission E recom-mends it for the
treatment of dyspeptic complaints, toxin-induced liver da-mage, and hepatic cirrhosis and as a
supportive therapy for chronic inflammatory liver conditions.6,7Further studies are needed to
evaluate milk thistle’s renal protectant effects, such as prevention of cisplatin toxicity, its use
in treating alcoholic liver disease, and its use to prevent cancer or as a complementary
treatment for cancer.
The bioavailability of enterally admi-nistered silymarin is limited; the compound is
poorly soluble in water, and only 20-50% is absorbed from the gastrointestinal tract after
ingestion. Absorption is significantly enhanced if silybin is administered in a complex with
phosphatidlycholine.8 Milk thistle silymarin has anti-inflammatory, cytoprotective, and
anticarcinogenic effects. These effects are probably related to inhibition of activation of NF-
kappa B and the kinases.9 Silybin, a major constituent of the milk thistle, is used to treat
several liver disorders. Its active ingredients appear to be several closely related flavinoids,
collectively known as silymarin. Most silymarin preparations have at least a dozen molecular
components and their isomers, including silybin, isosilybin, cis-silybin, silydianin, and
silychristine. A safe and effective, broad-spectrum hepatopro-tective agent would likely be
very useful in the management of liver disease. Yet, despite its clear effects in experimental
animal models, silymarin has yet to be proven effective in ameliorating human liver
disease.10,11 Milk thistle silybin inhibited RNA and protein synthesis on gram-positive
bacteria.12 Milk thistle, silymarin, reduced NO production at less than 300 ppm.13 Milk
thistle silymarin exerts chemopreventive effects against tumorigenicity by inhibiting
endogenous tumor promoter TNF alpha.14 Milk thistle is hepatoprotective in many
experimental models of liver damage. It protects in three ways: by enhancing DNA
polymerase, stabilizing cell membranes and scavenging free radicals.15 Although regarded as
safe, many of the extract constituents remain thus far untested for their possible effects on
liver biotransformation enzymes. Cyto-chromes P450 (CYP) are very important in this regard.
Scientists Tested the effect of four flavonolignans: silybin, its hemisynthetic derivative
dehydrosilybin, silydianin, and sily-cristin on three specific CYP activities: bufuralol 1′-
hydroxylation (CYP2D6), p-nitrophenol hydroxylation (CYP2E1), and nifedipine oxidation
(CYP3A4).7 All flavonolignans displayed, an inhibition that was not considered to be
relevant for therapy. The data support the use of the extract as a dietary supple-ment.16Unlike
those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected
by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically
relevant effect on CYP3A activity in vivo.17 S. marianum is well tolerated in subjects with
CHC, but does significantly affect serum HCV RNA, alanine aminotransferase levels, quality
of life or psychological well-being in subjects with this condition.18 Many scientists point out
the anticancer potential of silymarin as it is able to suppress the proliferation of tumour cells
(prostate, breast, ovary, colon, lung and bladder).19,20 Silymarin has had a good safety record
and only in rare cases have there been reports of gastrointestinal disturbances (nausea and
epigastric discomfort), arthralgia, headache, and allergic skin rashes.21,22 In rats, silybin
prevented cisplatin-induced glomerular and tubular nephrotoxicity as measured by BUN,
creatinine and fibronectin and histo-logical changes in renal tubules.23 Similarly, in rats,
silymarin and silybin counteracted alcohol toxicity to the liver, as measured by serum gamma
glutamyl transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase
(AST) activity.24 In a randomized, placebo controlled double blind trial of 60 women
receiving chronic psychotropic therapy (butyrophenones or phenothiazines) who had
increased AST and ALT, those who received silymarin (800 mg daily in two divided doses)
for 90 days had reduced lipoperoxidative hepatic damage compared to those who received
placebo; this protective effect was greater when treatment with psychotropic drugs was also
suspended.25 In a placebo – controlled trial in 60 alcoholics with hepatic cirrhosis and insulin
resistant / dependent diabetes, those treated with silymarin (Legalon ® 200 mg three times
daily) had significant decreases in fasting glycemia, mean daily blood glucose, glycosuria,
and insulin needs over six months.26 In a doubleblind, placebo-controlled trial of 40 patients
with alcoholic cirrhosis, treatment with silymarin increased lectin-induced lymphoblast
transformation, decreased the percentage of OKT8+ cells and suppressed lymphocytotoxicity
signifi-cantly more than in the placebo treated group.27 In patients with alcoholic cirrhosis,
silymarin enhanced erythro-cyte and lymphocyte levels of super-oxide dismutase, thereby
enhancing antioxidant effects.28
Results of studies in experimental animal models suggest that silymarin has a broad
spectrum of hepatopro-tective effects. Thus, silymarin can protect experimental animals
against injury from several toxins, including amanita phalloides, carbon tetra-chloride,
ethanol, and galactosamine. Silymarin is partially protective even when given after exposure.
The basis for this hepatoprotective activity may be the antioxidant qualities of the several
flavinoids, but antifibrotic, antiinflammatory and immune modu-latory actions of silymarin
may also be important.9 Silymarin does not reduce mortality and does not improve
biochemistry and histology among patients with chronic liver disease; however, it appears to
be safe and well tolerated. Pretreatment with silymarin prevented post-ischemic mucosal
injury. These results suggest that neutrophils play an important role in the gastric mucosal
dysfunction associated with ischemia-reperfusion. These findings also indicate that the
inhibitory effects of silymarin on neutrophil function may contribute significantly to its
gastroprotective actions.Though silymarin does not have antiviral properties against hepatitis
virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation,
enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to
be a useful drug for hepatoprotection in hepatobiliary di-seases and in hepatotoxicity due to
drugs. The non traditional use of silymarin may make a breakthrough as a new approach to
protect other organs in addition to liver. Although the mechanism of action is not fully
understood, one explanation may be that it concentrates in the hepatocytes and competes with
toxins for hepa-tocyte binding and penetration. Stan-dardization of herbal medicines has been
a problem and prospective, randomized, placebo-controlled clinical trials are lacking to
support their efficacy. The methodological qualities of clinical trials of treatment with herbal
preparations are poor. Reputable herbalists recommend a range of doses. Amounts used in
studies range from 280 mg to 800 mg of silymarin daily. Most studies have used a
concentrated, standardized product containing 70-80% silymarin. Studies using a
silybinphospha-tidylcholine complex have used dosages of 100 mg three times daily because
absorption is enhanced with this preparation.29 There is one case report of a British woman
who apparently had a severe allergic reaction to a milk thistle capsule; it was unclear whether
the reaction was to milk thistle or some other ingredient in the capsules.30 But tea is not the
preferred route of administration since silymarin is poorly soluble in water, but if the milk
thistle seeds are roasted and broken open they can be used as tea. The usual dose is 12-15
grams of roasted, cracked seeds divided into three doses daily, taken with meals.31 Tincture:
3-6 ml (about 1/2-1 tsp.) three times daily with meals.
Despite a modest sample size and multiple etiologies for acute clinical hepatitis, our
results suggest that standard recommended doses of silymarin are safe and may be potentially
effective in improving symptoms of acute clinical hepatitis despite lack of a detectable effect
on biomarkers of the underlying hepato-cellular inflammatory process. This suggests that the
antioxidant and free radical scavenging properties may account for most of the therapeutic
effect of these compounds. The untoward effect of silymarin on cultured cells may have
consequences when considering long-term prescription of this therapeutic agent.
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