Life Extension Magazine June 2003
A New Era for SAMe
SAMe and liver cirrhosis
The liver is Grand Central Station for molecules that chaperone lipids around the body. It is the site where very low-density lipoproteins (VLDL) and cholesterol are synthesized. Despite the general misconception that cholesterol is inherently bad, it is actually a very important substance that functions as the precursor for important steroid hormones such as estrogen, DHEA, androgens and the glucocorticoids. It also is part of bile, which acts as a natural detergent against dietary fat.24
Cirrhosis of the liver is a chronic, diffuse degenerative disease (most commonly induced by alcohol abuse) in which the lobules are infiltrated with fat and structurally altered, resulting in a localized loss of function and an increased resistance to blood flow through the damaged area. Although about a third of all cases are compensated, meaning that there are no clinical symptoms, severe cases of cirrhosis can lead to ammonia toxicity, hepatic coma, gastrointestinal hemorrhage, kidney failure and eventually death.25
Research has shown that SAMe can prevent and, if discovered early enough, even reverse this condition. In a rodent study published in Toxicology and Applied Pharmacology, SAMe completely prevented fatty liver when given at the same time as alcohol.26 Not only does SAMe prevent fat from accumulating in the liver, it prevents cirrhosis-related lipid elevation outside of the liver. Studies have found that the blood cells in people with cirrhosis have a high cholesterol-to-phospholipid ratio, a factor that causes problems with the way liver cells function.27 A group in England recently showed that SAMe dramatically reduces cholesterol and re-establishes healthy levels. That study found that the cholesterol-to-phospholipid ratio decreased substantially in the erythrocytes of people with liver disease two weeks after they were treated orally with 1,600 mg of SAMe.28
The cancer connection
It has long been thought that alterations in the liver caused by alcohol, toxins and diseases can eventually lead to cancer. The proof behind this theory began to appear in 1988, when a team of Spanish researchers studying cirrhosis discovered that it is directly related to deficiencies of S-adenosylmethionine synthetase and phospholipid methyltransferase, two important enzymes that convert methionine to SAMe and form phospholipids.29 Later studies by researchers at the University of Southern California further revealed that liver cancer cells are totally lacking in liver-specific SAMe synthetase; the genes for this enzyme are completely turned off in liver cancer patients.30 A group at the Institute of Biomedical Investigation in Spain further elucidated the relationship between SAMe synthetase and cancer. Their study found that the immune substance interleukin-2 (IL-2) turns on the SAMe synthetase gene in T-cells. IL-2 is necessary for the growth of immune cells that fight viruses and cancer.31
It is well established that methyl deficiency produces liver cancer in rodents. Methyl deficiency causes a reduction in SAMe levels and a subsequent elevation in S-adenosylmethionine homocysteine (SAH).33 SAH is what remains after SAMe donates a methyl group for biochemical reactions. An enzyme, SAH hydrolase, turns SAH into homocysteine. Homocysteine can be toxic if it builds up within the body, but is typically converted into cysteine (and eventually glutathione) when enough SAMe is present. If, however, SAMe levels are extremely low, nothing gets converted and SAH and homocysteine levels rise. This is when cancer gets its toehold. A low SAMe-to-SAH ratio is step number one in the development of liver cancer. However, re-establishing adequate SAMe levels can reverse the early changes in the process.34
Finally, cancer suppressor genes also are adversely affected by under-methylation. Researchers at the FDA's National Center for Toxicological Research have conducted research showing how under-methylation affects the p53 tumor suppressor gene. They have found that rats fed a diet deficient in SAMe precursors (methionine, choline and folic acid) accumulate DNA strand breaks in certain areas of the p53 gene within days. DNA strand breaks translate into a defective or non-functioning p53 protein. Without p53 to stop them, some types of cancer cells will run wild.35
Other liver disorders respond to SAMe
It seems that almost any liver disease may be improved with SAMe therapy. Cholestasis, for example, is a common condition of insufficient bile. While this problem may not generate as much awe and public scrutiny as cancer, nonetheless it can be a serious condition resulting in anything from painful gallstones to death.36
Among the usual causes of cholestasis are estrogen-replacement therapy, birth control pills, certain drugs (including antidepressants) and pregnancy. Studies into the effects of SAMe on cholestasis have found that it protects against this disorder at oral doses of between 600 mg and 800 mg per day.1 These findings were further supported by the recent U.S. government study, which concluded that SAMe is an effective treatment of cholestasis during pregnancy.
The prevention of liver disease is just as important as the prevention of heart disease and cancer. Like these two killers, liver diseases can be prevented by simple yet very effective dietary means. No person escapes liver damage. Chemicals in air and water, drugs, radiation, pesticides, hormones and drugs in meat, fungicides on grains, bacteria, parasites and other entities constantly assault us. The liver must deal with all of them on a daily basis. It generates a massive amount of free radicals during detoxification. Helping the liver is one of the simplest and most important steps persons can do for their health. It is very likely that many diseases in other organs begin when the liver can't do its job.
The future of SAMe
Obviously, SAMe's importance to maintaining biological stability cannot be overstated. Clear evidence exists showing that SAMe is an effective treatment for many age-related disorders including depression, arthritis and liver disease. But researchers aren't stopping there. Currently, studies are underway examining the relationship between SAMe deficiency and numerous other diseases associated with advanced age, such as cancer, Parkinson's disease, Alzheimer's disease, heart disease, Addison's disease, senile dementia and sleep disorders. Considering the far-reaching effects already discovered about this extraordinary compound, undoubtedly it will soon become a major focus of supplemental medicine.
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1. S-Adenosylmethionine for treatment of depression, osteoarthritis and liver disease. Summary, Evidence Report/Technology Assessment: Number 64. AHRQ Publication No. 02-E033, August 2002. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/samesum.htm.
2. Elkins, R. SAMe: The Remarkable Substance that Promotes Detoxification, Relieves Arthritis and Fights Depression. Pleasant Grove, UT; Woodland Publishing, 1999, 5-6.
3. Momparler RL, et al. DNA methylation and cancer. J Cell Physiol 2000 May;183(2):145-54.
4. Brown R, et al. S-Adenosylmethionine (SAMe) for depression. Psychiatric Annals 2002 Jan 1;32:29-44.
5. Brown R, et al. Stop Depression Now. New York, NY; Berkley Books, 1999, 64.
6. Davidson JR, et al. The underrecognition and undertreatment of depression: what is the breadth and depth of the problem? J Clin Psychiatry 1999;60 Suppl 7:4-9; discussion 10-1.
7. Warrington SJ, et al. The cardiovascular effects of antidepressants. Psychol Med Monogr Suppl 1989;16:i-iii, 1-40.
8. Elkins, R. SAMe: The Remarkable Substance that Promotes Detoxification, Relieves Arthritis and Fights Depression. Pleasant Grove, UT; Woodland Publishing, 1999, 10.
9. De Vanna M, et al. Oral S0adenosylmethionine in depression. Current Therapeutic Research. 1992;52:478-485.
10. Rosenbaum JF, et al. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand 1990 May;81(5):432-6.
11. Jandric S. Etiology, pathophysiology and conservative therapy of degenerative rheumatic diseases. Med Pregl 2002 Jan-Feb;55(1-2):35-9.
12. Singh G, et al. Prevalence of cardiovascular disease risk factors among U.S. adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care 2002 Oct;8(15 Suppl):S383-91.
13. Hinton R, et al. Osteoarthritis: diagnosis and therapeutic considerations. Am Fam Physician 2002 Mar 1;65(5):841-8.
14. Pomp E. A critical evaluation of side effect data on COX-2 inhibitors. Tidsskr Nor Laegeforen 2002 Feb 20;122(5):476-80.
15. Polli E, et al. Pharmacological and clinical aspects of S-adenosylmethionine (SAMe) in primary degenerative arthropathy (osteoarthrosis). Minerva Med 1975 Dec 5;66(83):4443-59.
17. di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med 1987 Nov 20;83(5A):60-5.
18. Gutierrez S, et al. SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells. Br J Rheumatol 1997 Jan;36(1):27-31.
19. Szabo G, et al. Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis 2002 Nov;6(4):1045-66, x.
20. Elkins, R. SAMe: The Remarkable Substance that Promotes Detoxification, Relieves Arthritis and Fights Depression. Pleasant Grove, UT; Woodland Publishing, 1999, 23.
21. Parcell S. Sulfur in human nutrition and applications in medicine. Altern Med Rev 2002 Feb;7(1):22-44.
22. Lieber CS. S-adenosylmethionine: its role in the treatment of liver disorders. Am J Clin Nutr 2002 Nov;76(5):1183S-7S.
23. Fernandez-Checa JC, et al. S-adenosylmethionine and mitochondrial reduced glutathione depletion in alcoholic liver disease. Alcohol 2002 Jul;27(3):179-83.
24. Kang S, et al. Cholesterol and hepatic lipoprotein assembly and secretion. Biochim Biophys Acta 2000 Dec 15;1529(1-3):223-30.
25. Baraona E, et al. Effects of ethanol on lipid metabolism. J Lipid Res 1979 Mar;20(3):289-315.
26. Feo F, et al. Effect of the variations of S-adenosylmethionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats. Toxicol Apl Pharmacol 1986 Apr;83(2):331-41.
27. Kakimoto H, et al. Altered lipid composition and differential changes in activities of membrane-bound enzymes of erythrocytes in hepatic cirrhosis. Metabolism 1995 Jul;44(7):825-32.
28. Rafique S, et al. Reversal of extrahepatic membrane cholesterol deposition in patients with chronic liver diseases by S-adenosylmethionine. Clin Sci (Lond) 1992 Sep;83(3):353-6.
29. Duce AM, et al. S-adenosylmethionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis. Hepatology 1988 Jan-Feb;8(1):65-8.
30. Cai J, et al. Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance. Hepatology 1996 Nov;24(5):1090-7.
31. Tobena R, et al. Interleukin-2 induces gamma-S-adenosylmethionine synthetase gene expression during T-lymphocyte activation. Biochem J 1996 Nov 1;319 ( Pt 3):929-33.
32. Seitz HK, et al. Alcohol and cancer. Recent Dev Alcohol 1998;14:67-95.
33. Pascale RM, et al. Chemoprevention of hepatocarcinogenesis: S-adenosylmethionine. Alcohol 2002 Jul;27(3):193-8.
34. Cai J, et al. Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res 1998 Apr 1;58(7):1444-50.
35. Pogribny IP, et al. De novo methylation of the p16INK4A gene in early preneoplastic liver and tumors induced by folate/methyl deficiency in rats. Cancer Lett 2002 Dec 10;187(1-2):69-75.
36. van Ooteghem NA, et al. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 2002 Mar;36(3):439-43.
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