Silymarin - Mechanism of Action

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Mechanism of Action

Silymarin has been reported to protect liver cells from a wide variety of

toxins, including

acetaminophen, ethanol, carbon tetra-chloride, and D-galactosamine.18-23

Silymarin has also been

found to protect liver cells from ischemic injury,24 radiation,25 iron

toxicity,26 and viral hepatitis.27

The mechanisms which provide silymarin's hepatoprotective effects are many

and

varied, and

include antioxidation,21,26,28 anti-lipid peroxidation,19,28,29 enhanced

detoxification,30-32 and

protection against glutathione depletion.33,23 Silymarin has been found to

inhibit the formation of

leukotrienes from polyunsaturated fatty acids in the liver, via its

inhibition

of the enzyme

lipoxygenase. These leukotrienes are known to be some of the most damaging

chemicals found in

man.34

Studies also demonstrated that silymarin increased hepatocyte protein

synthesis,35,36 decreased

the activity of tumor promo-ters,37 stabilized mast cells,38 modulated

immune

functions,39,40 and

was anti-inflam- matory41-43 and antifibrotic.44-46

Stimulation of Liver Regeneration: One of the mechanisms to explain the

ability

of silymarin to

stimulate the regeneration of hepatic tissue is the increase in protein

synthesis in damaged livers.

In both in vivo and in vitro experiments, significant increases in the

formation

of ribosomes and

DNA synthesis were measured in addition to the increase in protein

synthesis.

Interestingly, the

increased protein synthesis was only measured in damaged livers (partial

hepectomy), not in

controls.35 The mechanism of increased protein synthesis is currently not

known

but some authors

speculate silymarin imitates a physiologic regulator, so the silybin fits

into a

specific binding site on

the polymerase, thus stimulating ribosome formation.36

The potential for stimulation of protein synthesis by silymarin was

investigated

in malignant liver

tissue, and no increases in protein synthesis, ribosome formation, or DNA

synthesis were found in

malignant cell lines.35

Anti-inflammatory Effects: The mainstays of the current medical management

of

nonviral chronic

hepatitis are immunosuppressive/anti-inflammatory medications (e.g.,

prednisone,

azathioprine).

While use of these drugs may be lifesaving, long-term use may result in

debilitating, life-threatening

side-effects. Doctors and patients need safe and effective alternative

anti-inflammatory

medications. Botanical anti-inflammatories may constitute such a group.

Silymarin has been shown to have significant anti-inflammatory effects on

hepatic tissue. Several

studies have demonstrated a variety of anti-inflammatory effects, including

mast

cell

stabilization,38 inhibition of neutrophil migration,47 Kuppfer cell

inhibition,43 strong inhibition of

leukotriene synthesis, and prostaglandin formation.41-43

Antifibrotic Effects: Hepatic stellate cells play a central pathogenic role

in

liver fibrogenesis. In

response to some fibrotic influences (e.g., chronic ethanol exposure, carbon

tetrachloride, etc.),

they proliferate and transform into myofibroblasts, which are responsible

for

the deposition of

collagen fibers in the liver. One recent study investigated the effect of

silybin on the

transformation of hepatic stellate cells into myofibroblasts. Silybin [10-4

mol/l concentration] was

found to reduce the proliferation of freshly isolated rat hepatic stellate

cells

by about 75 percent.

It also reduced the conversion of stellate cells into myofibroblasts and

down-regulated the gene

expression of extracellular matrix components necessary for fibrosis.44

Silymarin has been shown to slow or reverse liver fibrosis in animals. Rats

were

subjected to a

complete bile duct occlusion which consistently causes progressive liver

fibrosis without

inflammation. Silymarin was able to reduce the fibrosis by 30-35 percent in

comparison with

controls (50 mg/kg/day, human dose = 3500 mg/day). Silymarin worked equally

if

used continuously

for six weeks after the bile duct occlusion or only for the final two weeks.

Dosage at 25 mg/kg/day

(human dose = 1750 mg/day) was not found to be effective.45

Colchicine is currently used to inhibit fibrosis of the liver. It functions

as

an antifibrotic and

anti-inflammatory by inhibiting macrophage stimulation of fibrosis.

Unfortunately, colchicine has a

narrow, unpredictable therapeutic window, and serious, life-threatening

side-effects, including

liver failure, renal failure, myocardial injury, severe gastrointestinal

damage,

shock, and death. In a

rat study using carbon tetrachloride-induced liver fibrosis, silymarin was

found

to be very similar to

colchicine for the prevention of chronic liver fibrosis, but without any

side-effects.46

Inhibition of P450: Paradoxically, silymarin may have an inhibitory effect

on

the cytochrome P450

(Phase I) detoxification system. In a recently published animal study,

silybin

was found to inhibit

several specific induced P450 enzymes in mice.30 Other researchers have

noted

the lack of

stimulatory effect on the P450 detoxification system.29,31 This effect may

explain some of the

hepatoprotective effects of silymarin, especially against Amanita poisoning.

Amanitin toxin

becomes deadly to hepatocytes only after it becomes bioactivated by the P450

system. The

inhibition of the bioactivation of amanitin could reduce its toxic effects.

In

addition, silymarin and

other antioxidants afford some protection against the free radicals

generated by

P450 enzymes.48

Enhanced Glucuronidation: Gluc-uronidation is an important Phase II liver

detoxification

pathway. More toxins are removed from the body via glucuronidation than any

other single

detoxification pathway.48 Glucuronic acid is conjugated with toxins to

facilitate their elimination

from the body via the bile. In addition, many other substances, including

estrogen, are removed

from the body via glucuronidation. Unfortunately, some intestinal bacteria

(mostly pathogenic)

possess an enzyme, beta-glucuronidase, that enables them to remove

glucuronic

acid from the

conjugated substance and use it as an energy source. This allows the

original

molecule to be

reabsorbed through the GI mucosa, thus re-exposing the person to the removed

substance.

Silymarin was found to inhibit the activity of beta-glucuronidase 53 percent

in

healthy humans

and in one patient with colon cancer.32

Immunomodulation: Researchers have investigated the immunomodulatory effects

of

silymarin on

the diseased liver. A pair of Hungarian studies demonstrated a positive

effect

of silymarin on

immune function. The first study looked at patients with histologically

proven

chronic alcoholic liver

disease. These patients originally had low T-cell percentage, high CD8+ cell

percentage, and an

enhanced antibody-dependent increase in lymphocyte cytotoxicity. All of

these

abnormal

immune findings were normalized by a six-month course of silymarin. No

significant changes were

found after six months in the control group.39

The second study looked at the hepatoprotective effect of silymarin in

addition

to its effects on

normalizing immune function. Forty patients with alcoholic cirrhosis of the

liver were given either

silymarin, amino-imidazole-carboxamide-phosphate, or placebo in a one-month,

double-blind

clinical trial. In the treated groups, silymarin normalized elevated levels

of

AST, ALT, and total

bilirubin, markedly reduced the high level of GGT, decreased the percentage

of

OKT8+ cells, and

suppressed lymphocytotoxicity.40

Dosage/Toxicity

Silybum marianum is not water soluble and is typically administered as an

encapsulated

standardized extract (70-80% silymarin). In animals, silymarin has proven to

be

non-toxic when

administered at high doses for short periods of time and long term dosage in

rats has also failed to

demonstrate any toxicity. Human studies have shown silymarin to be generally

without

side-effects. The typical adult dosage for silymarin is 240-900 mg/day in

two or

three divided doses.

At higer doses (>1500 mg/day) silymarin may produce a laxative effect due to

increased bile flow

and secretion. Mild allergic reactions have also been noted, but neither of

these side-effects was

severe enough to discontinue treatment.49-51

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