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Milk thistle flavonoids in the treatment of liver diseases

It is difficult to classify milk thistle preparations into any specific group of medicines.

When talking about milk thistle, they often say that it has “hepatoprotective” properties.

However, the legitimacy of identifying a separate pharmacological class of “hepatoprotectors” is questionable. The very concept of “hepatoprotectors” is, by definition, not strict and is interpreted quite arbitrarily by different specialists. In the most common understanding, this is a class of drugs that, regardless of the mechanism of action, increase the functional ability of liver cells to synthesize, detoxify and excrete various biological products, and support the resistance of hepatocytes to various pathogenic influences.

The general nature of the name “hepatoprotectors” apparently reflects the insufficient depth of our knowledge about the pathogenesis of liver diseases, the mechanisms of damage, regeneration, fibrosis and malignant transformation of hepatocytes.

In many reference books and manuals, the class of “hepatoprotectors” includes activators of protein synthesis (bemitil), vitamins, nucleic acid precursors, drugs that stimulate detoxification reactions in the liver (asparagine, glutamine, citrulline), metabolites of mitochondrial respiration (malic acid, sodium succinate, cytochrome , carnitine, aminalon), drugs that reduce the proapoptotic effect of bile acids (ursodeoxycholic acid), sulfhydryl group donors (S-adenosyl-L-methionine), drugs of essential phospholipids, lipoic acid.

At the same time, it is appropriate to recall that a number of drugs of this type (mainly of plant origin) have historically firmly taken their place in the therapy of internal diseases.

Among the “hepatoprotectors”, a very significant share is occupied by preparations containing natural or semi-synthetic flavonoids of milk thistle (Silybum marianum)

. The main active ingredient in them is silymarin.

Silymarin is a mixture of three main isomeric compounds - silicristin, silydianin and silibinin. The latter prevails in quantitative content and has the highest biological activity.

Are milk thistle preparations really capable of having a therapeutic effect on liver diseases?

The positive effects of silymarin in liver diseases are traditionally associated with a pronounced antioxidant potential, as well as the so-called “membrane stabilizing” effect.

The role of oxidative stress in the pathogenesis of liver diseases has been intensively studied in recent years. The production of reactive oxygen species (peroxides, superoxide anion radicals) is a common phenomenon in the process of cellular respiration, but their content increases excessively under conditions of alcohol intoxication, liver damage and inflammation, deficiency of antioxidants, hypoxia, and exposure to certain drugs. Increased production of free radicals is accompanied by damage to cellular organelles and macromolecules (DNA, proteins and lipids, antioxidant systems). Under oxidative stress, peroxidation products play an important role in fibrogenesis by activating hepatic stellate cells and increasing extracellular matrix production.

Intracellular “protective molecules” that prevent the development of peroxidation reactions include enzymes superoxide dismutase, catalase, glutathione peroxidase, metal-binding proteins, “free radical scavenger” molecules (glutathione, ubiquinones, uric acid, ascorbic acid and tocopherol, lipoic acid, selenium, riboflavin , zinc, carotenoids). The metabolism of various antioxidants is closely interrelated.

In conditions of liver inflammation, the source of production of reactive oxygen species is the cells of the inflammatory infiltrate.

In addition, one of the universal mechanisms of cell damage in liver diseases is impaired mitochondrial function.

When a cell is exposed to certain substances, such as tumor necrosis factor-a (TNFa), ethanol, as well as under conditions of excessive accumulation of iron and copper, the process of oxidative phosphorylation in mitochondria is disrupted, which is accompanied by the development of energy deficiency and cell death.

Disorganization of mitochondrial membranes under conditions of peroxidation may be accompanied by a “leakage” of cytochrome C into the cytoplasm and activation of the process of programmed cell death.

Despite the fact that modern scientific data regarding the importance of free radical processes in the pathogenesis of liver diseases are often contradictory, in certain clinical situations the negative pathogenetic role of mitochondrial dysfunction, cellular respiration and the development of lipid peroxidation is beyond doubt. These are primarily alcoholic liver disease, non-alcoholic steatohepatitis, intrahepatic cholestasis of pregnancy, and some cases of toxic liver damage.

The antioxidant effect of silymarin is due to its interaction with free radicals in the liver and converting them into less aggressive compounds. This interrupts the process of lipid peroxidation and prevents further destruction of cellular structures. The ability to interact with reactive oxygen species is due to the presence of a phenolic structure in the silibinin molecule.

The antioxidant effect of silymarin and inhibition of peroxidation reactions have been clearly demonstrated in vitro. Milk thistle flavonoids exhibit 10 times higher antioxidant activity than tocopherol.

Due to the presence of antioxidant properties, milk thistle preparations exhibit anti-inflammatory activity

. The therapeutic effect of silibinin was demonstrated in models of toxic liver damage in rats caused by the administration of carbon tetrachloride. In an acute experiment, with a single administration of carbon tetrachloride, the administration of milk thistle flavonoids was accompanied by a clear decrease in the severity of cytolysis and cholestasis. In a chronic experiment with carbon tetrachloride, the administration of silibinin also contributed to a significant reduction in the severity of cytolysis and cholestasis.

It is no coincidence that workers in hazardous chemical industries are recommended to take prophylactic silymarin once a day.

Milk thistle flavonoids have the most striking therapeutic effect on alcoholic liver disease.

Hungarian researcher Muzes G. et al. in a double-blind study showed that silymarin has a positive clinical effect in alcoholic liver disease

, apparently due to the antioxidant effect of this substance. Prescription of silymarin in a daily dose of 420 mg per day for 6 months. was accompanied by biochemical changes in the body, which indirectly indicate an increase in the antioxidant potential of cells and blood serum. Thus, there was a significant increase in the activity of superoxide dismutase in enterocytes and lymphocytes (with initially reduced values), an increase in the activity of glutathione peroxidase and the content of substances with sulfhydryl groups in the serum. At the same time, there was a significant decrease in the concentration of substances exhibiting oxidizing properties (malondialdehyde, etc.) in the blood serum.

For viral hepatitis C, according to Berkson BM, the administration of a “triple antioxidant regimen” (thioctic acid, silymarin, selenium) is a fairly cheap and safe method of pathogenetic treatment of viral hepatitis C and inhibition of the progression of liver damage to the stage of cirrhosis. The antioxidant effect of therapy helps suppress the inflammatory-necrotic reaction in the liver, inhibit the development of fibrosis and reduce the risk of malignant transformation of hepatocytes.

Also interesting are data on the immunomodulatory properties of milk thistle flavonoids in alcoholic liver disease. Their long-term administration (about 6 months) helps to reduce the activity of the cytotoxic link (the content of cytotoxic CD8+ lymphocytes), reduce the production of g-globulins and increase the rate of blast transformation of lymphocytes.

A number of authors consider it advisable to prescribe silymarin to patients suffering from hepatitis C, if they need to take drugs that can reduce the antioxidant potential of hepatocytes (for example, acetaminophen).

For intrahepatic cholestasis of pregnancy, the use of silymarin can reduce the severity of skin itching.

Silymarin “stabilizes” hepatocyte membranes, reducing the cells’ susceptibility to certain pathogenic influences.

Blockade of phosphodiesterase under the influence of milk thistle flavonoids helps slow down the breakdown of cyclic adenosine monophosphate (cAMP), and, as a result, reduce the calcium content inside cells, inhibiting the calcium-dependent process of activation of phospholipases.

Silibinin has the ability to block the corresponding binding sites on the cell membrane and transport systems that facilitate the transfer of toxic substances across the membrane. This is the main mechanism of the therapeutic effect of silibinin in case of poisoning with toadstool (counteracting the poison a-amantine). To treat patients with such poisonings, a readily soluble form of silibinin for intravenous administration (dihydrosuccinate sodium salt) has been developed.

An important aspect of the metabolic action of milk thistle flavonoids is also the ability to stimulate protein synthesis and support the process of hepatocyte regeneration. Silibinin stimulates RNA polymerase I in the cell nucleus, activates transcription and the rate of RNA synthesis.

At the same time, the rate of DNA transcription in malignant cells, as well as the rate of their division, does not increase, which excludes the possibility of stimulating tumor growth when prescribing milk thistle preparations.

There is evidence of a slowdown in the rate of progression of liver fibrosis during long-term use of silibinin.

Unfortunately, the anti-inflammatory and antifibrotic effects of milk thistle preparations are currently not confirmed by the results of multicenter randomized controlled trials, and the available data are obtained from the results of individual observations. The effectiveness of silymarin should be assessed according to the principles of evidence-based medicine.

It is advisable to prescribe milk thistle derivatives to patients suffering from liver diseases (mostly chronic): hepatic steatosis, acute or chronic hepatitis, cirrhosis of various etiologies. Caution should be exercised when prescribing them to patients with clearly defined intrahepatic cholestasis: there is information about the possibility of increasing bile stagnation under the influence of drugs.

It has been noted that both acute and chronic liver diseases are often accompanied by the development of concomitant biliary dyskinesia. Biliary dyskinesia is the leading cause of pain in the epigastric region and right hypochondrium with steatosis, hepatitis and cirrhosis of the liver, often with characteristic irradiation to the right half of the chest, right shoulder blade and a clear connection with the intake of fatty, fried foods.

The development of biliary tract motility disorders often dictates the need to prescribe to the patient drugs that have a mild antispasmodic effect on the smooth muscle cells of the biliary system.

Silymarin directly has choleretic properties due to the presence of both choleretic and cholekinetic effects. Choleresis develops due to increased secretion of bile acids and electrolytes by hepatocytes. The cholekinetic effect is associated with a decrease in the tone of the biliary sphincters.

However, many of the drugs, the main active ingredient of which are milk thistle flavonoids, contain components of other medicinal plants that have a combined effect on the composition and outflow of bile: moderate choleretic, antispasmodic, anti-inflammatory and antiseptic effects.

The main active ingredient from the family of medicinal flavonoids of milk thistle - silibinin - is included in various drugs: Sibektan, Legalon, Siromin, etc. The differences between these drugs consist in the quantitative ratios of flavonoids, as well as in combinations of milk thistle with other drugs, usually having a choleretic or antiseptic effect.

The drug Sibektan

contains dry extract of tansy, milk thistle fruits, St. John's wort and birch.

St. John's wort herb contains tannins from the catechin group (tannins, flavonoids, essential oils), which have an astringent and anti-inflammatory effect on the mucous membrane of the gastrointestinal tract.

Tansy flowers also contain various flavonoids, essential oils and organic acids, which have a choleretic effect (increase the contractile activity of the gallbladder).

Birch leaf extract also has an antiseptic, mild choleretic and distinct diuretic effect.

Sibektan is successfully used in the treatment of chronic cholecystitis and hypotonic dyskinesia of the gallbladder. It is prescribed for hepatitis and cirrhosis of the liver to prevent the progression of the process.

Considering the presence in the drug of substances with quite pronounced cholekinetic activity that can enhance the motor function of the gallbladder, Sibektan should be prescribed with caution in case of cholelithiasis.

Milk thistle flavonoid preparations are prescribed mainly orally, half an hour before meals. They are quickly and completely absorbed from the gastrointestinal tract. Plasma protein binding is weak. Excreted mainly in bile, to a lesser extent in urine; the half-life is about 6 hours. They are actively included in the enterohepatic circulation, which seems to be an advantageous pharmacokinetic parameter.

The duration of treatment courses is from 25 days to 1.5 months. Repeated courses are possible.

Numerous studies have established that milk thistle preparations belong to the category of low-toxic substances and in therapeutic doses do not have a damaging effect on the main organs and systems of the animal and human body.

When prescribing, the possibility of developing allergic reactions to plant components should be taken into account.
Literature:
1. FARMIndex: PRACTITIONER, issue 3 – St. Petersburg: FARMIndex LLC, 2002 – 136 p.

2. Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin 1999 Oct 15;94 Suppl 3:84–9.

3. Deak G, Muzes G, Lang I, et al. Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 131:1291–1292;1990.

4. Feher J, Deak G, Muzes G, et al. Liver–protective action of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 130:2723–2727; 1989.

5. Ferenci P, Dragosics B, Dittrich H, Frank H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9:105–113; 1989.

6. Lang I, Nekam K, Deak G, et al. Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers. Ital J Gastroenterol 22:283–7; 1990.

7. 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 centers. Med Klin 73:1060–1065; 1978.

8. Muzes G, Deak G, Lang I, et al. Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol). Orv Hetil 131:863–866; 1990.

9. Reyes H, Simon FR. Intrahepatic cholestasis of pregnancy: an estrogen–related disease. Semin Liver Dis 13:289–301; 1993.

10. Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double–blind controlled study. Scand J Gastroenterol 17:517–521; 1982.