MILK THISTLE #4

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Description and Constituents

Silybum marianum (milk thistle) has been used for centuries as an herbal

medicine for the treatment of liver disease. Its use for liver disorders

dates back to Pliny the Elder, a Roman naturalist, who described milk

thistle as being " excellent for carrying off bile. " 1 Milk thistle is an

annual or biennial plant indigenous to Europe and is also found in some

parts of the United States. It grows in rocky soils to a height of three to

ten feet with an erect stem that bears large, alternating, prickly-edged

leaves. The common name, milk thistle, is derived from the " milky white "

veins on the leaves, which, when broken open, yield a milky sap. Flowering

season is from June to August, and each stem bears a single, large, purple

flower ending in sharp spines. The fruit portion of the plant is glossy

brown or grey with spots.2-4 Silybum marianum contains silymarin, which is

composed of the flavanolignans silybin, silydianin, and silychristine, with

silybin being the most biologically active. Silymarin is found in highest

concentrations in the fruit portion of the plant but is also found in the

leaves and seeds. The seeds also contain betaine, trimethylglycine and

essential fatty acids, which may contribute to silymarin's hepatoprotective

and anti-inflammatory effects.

Mechanisms of Action

Silymarin's hepatoprotective effects are accomplished via several mechanisms

including antioxidation,8 inhibition of lipid peroxidation,9 enhanced liver

detoxification via inhibition of Phase I detoxification and enhanced

glucuronidation,10,11 and protection of glutathione depletion.12 Studies

have also shown silymarin exhibits several anti-inflammatory effects,

including inhibition of leukotriene and prostaglandin synthesis, Kupffer

cell inhibition, mast cell stabilization, and inhibition of neutrophil

migration.13-17 In addition, silymarin has been shown to increase hepatocyte

protein synthesis, thereby promoting hepatic tissue regeneration.18 Animal

studies have also demonstrated silybin reduces the conversion of hepatic

stellate cells into myofibroblasts, slowing or even reversing fibrosis.19

Clinical studies conducted in Hungary also demonstrated silymarin to have

immunomodulatory effects on the diseased liver.20,21

Pharmacokinetics

Silymarin is not water soluble, making tea preparations ineffective;

therefore it is usually administered orally in encapsulated form. Because

absorption of silymarin from the gastrointestinal tract is only moderate

(23-47%), it is best administered as a standardized extract of 70-80 percent

silymarin. In animals and humans, peak plasma levels are reached in four to

six hours after an oral dose. Silymarin is excreted primarily via the bile

but some clearance is also achieved via the kidneys. The clearance half-life

of silymarin is six to eight hours.22,23

Clinical Indications

Amanita Mushroom Poisoning

The most impressive use of silymarin is in the treatment of Amanita

phalloides mushroom poisoning. The genus Amanita is widespread in Europe and

North America with several edible species being prized by mushroom

collectors. Unfortunately, many of the Amanita species are highly toxic, and

ingestion results in severe liver damage and death in approximately 30

percent of cases.24 In animal studies, silymarin given within 10 minutes

after amanita toxin ingestion completely counteracted the toxic effects, and

if given within 24 hours of toxin ingestion silymarin prevented death and

greatly reduced liver damage.25

Hepatitis

Studies have shown silymarin to be effective in the treatment of both acute

and chronic hepatitis. In acute viral hepatitis, administration of silymarin

shortened treatment time and lowered serum bilirubin, AST, and ALT. In

patients with chronic hepatitis, 420 mg silymarin per day for six months

also yielded improved serum liver enzymes.26

Alcoholic Liver Disease and Cirrhosis

Studies conducted in Austria and Hungary have demonstrated silymarin

administration resulted in a normalization of serum liver enzyme and total

bilirubin levels in patients with alcoholic liver disease, in addition to

improved liver tissue histology.27 In patients with cirrhosis, long-term (41

months) administration of silymarin at 420 mg per day resulted in a

significant increase in survival compared to the placebo group.28

Hypercholesterolemia

An animal study found silymarin given to rats with diet-induced

hypercholesterolemia demonstrated an anticholesterolemic effect similar to

probucol, with an increase in HDL cholesterol and a decrease in total and

biliary cholesterol.29

Psoriasis

The value of silymarin in the treatment of psoriasis may be due to its

ability to improve endotoxin removal by the liver, inhibit cAMP

phosphodiesterase, and inhibit leukotriene synthesis. Abnormally high levels

of cAMP and leukotrienes have been observed in patients with psoriasis and

normalization of these levels may improve the condition.13,30

Dosage/Toxicity

Silybum marianum is usually given as a standardized extract (70-80%

silymarin) in encapsulated form, 100-300 mg three times daily being the

typical adult dose. Both animal and human studies have shown silymarin to be

non-toxic. At high doses (>1500 mg per day) a laxative effect is possible

due to increased bile secretion and flow. Mild allergic reactions have also

been noted but were not serious.

References

1. Pliny the Elder, Historia Naturalis 77 A.D.

2. Bisset N. Herbal Drugs and Pharmaceuticals. London: CRC Press;

1994:121-123.

3. Gruenwald J, Brendler T, Jaenicke C. PDR for Herbal Medicines. Montvale,

NJ: Medical Economics Company, Inc.; 1998:1138-1141.

4. Luper S. A review of plants used in the treatment of liver disease: part

1. Altern Med Rev 1998;4:410-421.

5. Wagner H. Antihepatotoxic flavonoids. In: Cody V, Middleton E, and

Harbourne JB eds. Plant Flavonoids in Biology and Medicine: Biochemical,

Pharmacological, and Structure-Activity Relationships. New York, NY: Alan R.

Liss, Inc.; 1986:545-558.

6. Adzet T. Polyphenolic compounds with biological and pharmacological

activity. Herbs Spices Medicinal Plants 1986;1:167-184.

7. Hikino H, Kiso Y, Wagner H, Feibig M. Antihepatotoxic actions of

flavonolignans from Silybum marianum fruits. Planta Medica 1984;50:248-250.

8. Wagner H. Plant constituents with antihepatotoxic activity. In: Beal JL,

Reinhard E eds. Natural Products as Medicinal Agents. Stuttgart:

Hippokrates-Verlag; 1981.

9. Bosisio E, Benelli C, Pirola O, et al. Effect of the flavanolignans of

Silybum marianum L. on lipid peroxidation in rat liver microsomes and

freshly isolated hepatocytes. Pharmacol Res 1992;25:147-154.

10. Baer-Dubowska W, Szaefer H, Drajka-Kuzniak V. Inhibition of murine

hepatic cytochrome P450 activities by natural and synthetic phenolic

compounds. Xenobiotica 1998;28:735-743.

11. Halim AB, el-Ahmady O, Hassab-Allah S, et al. Biochemical effect of

antioxidants on lipids and liver function in experimentally-induced liver

damage. Ann Clin Biochem 1997;34:656-663.

12. Campos R, Garido A, Guerra R, et al. Silybin dihemisuccinate protects

against glutathione depletion and lipid peroxidation induced by

acetaminophen on rat liver. Planta Med 1989;55:417-419.

13. Fiebrich F, Koch H. Silymarin, an inhibitor of lipoxygenase. Experentia

1979;35:150-152.

14. Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as

an explanation for the hepatoprotective properties of silibinin. Hepatology

1996;23:749-754.

15. Fantozzi R, Brunelleschi S, Rubino A, et al. FMLP-activated neutrophils

evoke histamine release from mast cells. Agents Actions 1986;18:155-158.

16. Dehmlow C, Murawski N, de Groot H, et al. Scavenging of reactive oxygen

species and inhibition of arachidonic acid metabolism by silibinin in human

cells. Life Sci 1996;58:1591-1600.

17. De La Puerta R, ez E, Bravo L. Effect of silymarin on different

acute inflammation models and on leukocyte migration. J Pharm Pharmacol

1996;48:968-970.

18. Sonnenbichler J, Zetl I. Biochemical effects of the flavanolignane

silibinin on RNA, protein and DNA synthesis in rat livers. In: Cody V,

Middleton E, Harbourne JB, eds. Plant Flavonoids in Biology and Medicine:

Biochemical, Pharmacological, and Structure-Activity Relationships. New

York, NY; 1986:319-331.

19. Fuchs EC, Weyhenmeyer R, Weiner OH, et al. Effects of silibinin and of a

synthetic analogue on isolated rat hepatic stellate cells and

myofibroblasts. Arzneimittelforschung 1997;26:643-649.

20. Deak G, Muzes G, Lang I. Immunomodulator effect of silymarin therapy in

chronic alcoholic liver diseases. Orv Hetil 1990:131:1291-1292, 1295-1296.

[Article in Hungarian]

21. Lang I, Nekam K, -Cabello R. Hepatoprotective and immunological

effects of antioxidant drugs. Tokai J Exp Clin Med 1990;15:123-127.

22. Schandalik R, Gatti G, Perucca E, et al. Pharmacokinetics of silybin in

bile following administration of silipide and silymarin in cholecystectomy

patients. Arzneimittelforschung 1992;42:964-968.

23. Tyler V. Herbalgram 1994;30:24-30.

24. Vogel G, Tuchweber B, Trost W. Protection by silibinin against Amanita

phalloides intoxication in beagles. Toxicol Appl Pharmacol 1984;73:355-362.

25. Desplaces A, Choppin J, Vogel G, Trost W. The effects of silymarin on

experimental phalloidine poisoning. Arzneimittelforschung 1975;25:89-96.

26. Magliulo E, Gagliardi B, Fiori GP. Results of a double blind study on

the effect of silymarin in the treatment of acute viral hepatitis, carried

out at two medical centres. Med Klin 1978;73:1060-1065. [Article in German]

27. Feher I, Deak G, Muzes G. Liver protective action of silymarin therapy

in chronic alcoholic liver diseases. Orv Hetil 1989;130:2723-2727. [Article

in Hungarian]

28. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial

of silymarin treatment in patients with cirrhosis of the liver. J Hepatol

1989;9:105-113.

29. Kreeman V, Skottova N, Walterova D, et al. Silymarin inhibits the

development of diet-induced hypercholesterolemia in rats. Planta Med

1998;64:138-142.

30. Kock HP, Bachner J, Loffler E. Silymarin: Potent inhibitor of cyclic AMP

phosphodiesterase. Meth Find Expel Clin Pharmacol 1985;7:409-413.

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