Monday, February 4, 2008

Milk Thistle: Liver Regenerator

Silymarin is the active constituent of the milk thistle seed. It consists of flavonolignans called: silibinin, silicrystin, and silidianin. Silibinin (also known as Silybin) makes up about 70% of Silymarin. Silymarin undergoes enterohepatic recirculation and has higher concentrations in liver cells. It is a potent inhibitor of tumor necrosis factor (TNF). TNF induces cytotoxicity, inflammation and apoptosis (cell death). These are effectively blocked by Silymarin. TNF is involved in the body's normal inflammation response. However, in certain diseases TNF is working overtime, causing cell death and damages healthy cells. This disregulation often occurs in diseases such as, Rheumatoid Arthritis. The way Silymarin works is unclear, it appears to work by facilitating cellular communication (intracellular signaling).

Silybin is an antioxidant, a free radical scavenger, and an inhibitor of lipid peroxidation. When an oxygen atom loses an electron, that electron floats around the body damaging tissues, cells or anything it comes in contact with. When an appliance, like a computer is plugged in and not grounded, and a power surge occurs, your computer is toast. Similarly, these electrons referred to as free radicals, damage cells and cause cell death.

In vitro, Silybin shows affinity for binding to P-glycoprotein. This protein is thought to be involved in the drug resistance of cancer cells. So by binding to this protein, which in essence protects cancer cells from being affected by drugs, it improves the efficacy of these drugs.
With respect to liver disease, Silymarin seems to cause an alteration of the outer hepatocyte (liver cell) cell membrane, preventing toxin penetration. It increases a protein called ribosomal protein synthesis, which stimulates liver regeneration and the formation of new hepatocytes. Silymarin might have antifibrotic, anti-inflammatory, and immunomodulating effects that could also be beneficial in liver disease.

Silymarin might protect against kidney damage. In vitro, it has been shown to protect the kidney cells from nephrotoxic drugs such as, acetaminophen, cisplatin, and vincristin. Silybin and Silicristin also appear to have a regenerative effect on kidney cells, similar to that on hepatic cells. It also seems to decrease insulin resistance, which in turn reduces blood glucose and lipid levels in patients with diabetes. Some research suggests that oxidative stress can contribute to pancreatic beta-cell dysfunction (these cells are responsible for producing insulin), reduced insulin secretion and insulin resistance. Silymarin is thought to reduce this oxidative stress.

Since so many drugs are metabolized by the liver, it has been a concern that this metabolism might be affected by Silymarin. Although it does seem to be an inhibitor of some liver enzymes, this inhibition does not so far seem significant with respect to drug metabolism.
In review, Silymarin is effective for liver disease, diabetes, and dyspepsia (acid reflux/heartburn). Normal dose is ranges from 100mg to 200mg of Silymarin 2-3 times a day.

Saturday, February 2, 2008

In Charge of Morale: SAMe Improves Health and Mood)

Research is finding more and more a correlation with various health conditions, including heart disease, and depression. Low levels of SAMe may have something to do with these disease states. Perhaps it is the common thread. SAMe is a naturally occurring molecule distributed throughout all body tissues and fluids. The concentration of SAMe is highest in childhood, decreasing with age. It plays an essential role in more than one hundred chemical reactions (involving enzymatic transmethylation). It contributes to the synthesis, activation, and/or metabolism of hormones, neurotransmitters, nucleic acid, proteins, phospholipids, and some drugs.

SAMe is produced endogenously by adenosine triphosphate (ATP) activation of methionine that is synthesized in the body or obtained from metabolism of dietary protein (e.g. meat). SAMe synthesis is closely linked to Vitamin B12 and Folate (also known as folic acid) metabolism. Deficiency of these vitamins can decrease SAMe concentrations in the Central Nervous System (CNS).

Although it seems to have antidepressant properties, its actual mechanism of action is unknown. It is associated however, with an increase in serotonin turnover (facilitates higher levels of serotonin to be found and used outside the cell) and elevated dopamine and norepinephrine levels. These are three major neurotransmitters that are related to mood. By altering cellular membrane fluidity (improves traffic in and out of the cell), it facilitates signal transduction across membranes and consequently increases the efficiency of receptor effector coupling (the neurotransmitter finds a parking space). Neuroimaging studies indicate that SAMe affects the brain similarly to conventional antidepressants.

There appears to be hepatic SAMe deficiency in liver disease. Exogenously, it may act as an essential nutrient by restoring biochemical factors that are depleted in people with liver dysfunction. People with acute or chronic liver disease lose the ability to synthesize SAMe from methionine. This might be due to low activity of methionine adenosyl transferase (MAT), the enzyme that converts methionine to SAMe. As a result, this can lead to deficiencies in cysteine and choline, as well as depletion of glutathione, which plays a major role in liver detoxification and antioxidant reactions (gets rid of free radicals which harm cells and ultimately kills cells). This depletion in turn, exacerbates liver disease. SAMe also has a gastric cytoprotective effect (protects the cells of the stomach).

As was mentioned there are over one hundred chemical reactions in which SAMe is involved in; the following is one of the more important reactions and one that is well understood:

SAMe-------->Homocysteine---->---(remethylated,via folate and B12)---->Methionine

Methionine coverts back to-------->SAMe


Through transulfuration converts to-------->Glutathione

If these reactions are uninterrupted the result is the production of more SAMe and Glutathionine (antioxidant). However, if for example, an individual is deficient in Vitamin B12, Folate or Vitamin B6 (pyridoxine); SAMe will be converted to homocysteine and the reaction ends there. This outcome is unwelcome since high levels of homocyteine are associated with renal and cardiovascular disease. Recent studies show no significant increases however under normal circumstances, to the contrary, adequate levels of SAMe seems to promote the formation of glutathione by converting homocysteine. Low levels of SAMe have actually been correlated with coronary artery disease. Doses of 1200mg per day are used in people with liver disease.

SAMe taken orally has low bioavailability (isn’t absorbed well) because of first pass effect (liver metabolism). That is why higher doses are required and should be taken on an empty stomach. Levels peak 3 to 5 hours post ingestion. Although well tolerated, common side effects may be: flatulence, nausea, vomiting, diarrhea, constipation, dry mouth, and headache. But these are rare and usually seen with higher doses. Clinical trials used a dose of 1600mg/day, but the normal range is between 400mg-1600mg/day in divided doses. People with fibromyalgia take 800mg/day. It is available intravenously, but seldom used, for depression.
Not recommended for bipolar disorder since it can at times exacerbate the mania part of this condition. It should not be used concomitantly with antidepressants. It could potentiate serotonergic effects and serotonin syndrome like effects. Avoid if you have Parkinson’s. It may reduce effectiveness of levodopa given for this disease. Also avoid taking dextromethorphan (cough syrups), meperidine and DO NOT USE with MAO inhibitors. The body must be clear of MAOs for at least 2 weeks. Also avoid tramadol.