Conditions Where Thiols (Sulfur) Could Be Used In Prevention
Plasma thiols (ALA, GSH or its precursors) have been shown to inhibit oxidation of LDL cholesterol (LDLs). Oxidation of LDLs is regarded as a contributing factor in atherosclerosis. Oxidized LDLs are chemotactic to monocytes, promoting their migration into the intima, their early appearance in the fatty streak, and their transformation and retention in the subintimal compartment as macrophages. Scavenger receptors on the surface of macrophages facilitate the entry of oxidized LDLs into these cells, transferring them into lipid-laden macrophages and foam cells. Oxidized LDLs are also cytotoxic to endothelial cells and may be responsible for their dysfunction or loss from the more advanced lesion.
Low serum thiol levels can predict morbidity in HIV-positive IV drug users. N-acetylcysteine (NAC), glutathione, and alpha-lipoic acid have been shown to interrupt the process of viral activation and CD4 cell death. Sulfur supplementation (as SAA or NAC) has been demonstrated to raise plasma thiol levels. In a recent study, the analysis of the daily urinary excretion of sulfate and urea of a group of 19 AIDS patients and 22 asymptomatic HIV-positive subjects confirmed that HIV-positive patients experience massive loss of sulfur. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to a negative balance of approximately 2 kg of cysteine per year, assuming the normal sulfate excretion (3 g of cysteine per day) is balanced by an adequate diet. The abnormally high sulfate/urea ratio suggests this process drains the glutathione pool. In addition to counteracting catabolism of sulfur, cysteine has also been used to rebuild the immune function of HIV-positive patients. The immune system is the first to suffer the effects of cysteine depletion and the impairment of immune functions in HIV-positive patients results, at least in part, from cysteine deficiency and depletion of the GSH pool.
To determine the therapeutic effect of SAA supplementation in HIV infection, 40 patients with antiretroviral therapy (ART) and 29 patients without ART were given treatment for seven months with approximately 600 mg NAC administered every other day. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T-cell functions, and the viral load. N-acetylcysteine caused a marked increase in NK cell activity and raised CD4 counts, serum albumin, and glutamine. The immunomodulating effect of NAC supplementation suggests the HIV-induced cysteine depletion may be a way in which the virus compromises the immune defense of the host.
Therapeutically Relevant Thiols
Glucosamine sulfate (GS) is an aminomonosaccharide (a combination of glutamine and glucose) combined with a sulfate group. Used to treat osteoarthritis, GS is concentrated in joint cartilage where it is a substrate for cartilage glycosaminoglycan (GAG) synthesis. GS supplements are derived from chitin, a substance found in the shells of shrimp, lobsters, and crabs. Synthetic glucosamine sulfate is also available. Glucosamine is currently sold as the sulfate, hydrochloride, N-acetyl, or chlorhydrate salt. Most of the clinical studies have used either the sulfate or chloride salt. Reviews of clinical trials and meta-analyses support the efficacy of glucosamine.
Exactly how glucosamine works is not fully understood. About 90 percent of orally administered glucosamine gets absorbed, although a significant portion is catabolized during first pass metabolism and free glucosamine is not detectable in the serum after oral intake (possibly because it is bound to plasma proteins). This has led some researchers to speculate it is the sulfate rather than the glucosamine that is the active constituent.
Sulfate is required for GAG synthesis and sulfate depletion inhibits GAG synthesis in human articular cartilage. Hoffer et al recently demonstrated that glucosamine increases serum and synovial sulfate concentrations. This effect was reversed with co-administration of acetaminophen. GAG synthesis in human articular cartilage is sensitive to the sulfate-depleting effects of drugs used in the treatment of rheumatoid arthritis and osteoarthritis. Interestingly, sulfate administration can also increase the clearance of acetaminophen in sulfate-deficient individuals, decreasing its toxicity but potentially reducing the analgesic effect. Increases in serum sulfate may also explain some of the therapeutic effects of MSM and DMSO.
Chondroitin sulfate (CS) is a member of the polysaccharides called GAGs. CS is made up of linear repeating units of D-galactosamine and D-glucuronic acid and is found in human cartilage, bone, skin, cornea, and the arterial wall. Sources used in nutritional supplements include bovine and pork cartilage, shark cartilage, and whale septum. Whereas glucosamine sulfate is thought to promote the formation and repair of cartilage, chondroitin sulfate is believed to promote water retention and elasticity in cartilage and inhibit enzymes that break down cartilage.
It was thought that oral chondroitin was not absorbed because of its large molecular size. However, in 1995 researchers found evidence that up to 15 percent of chondroitin is absorbed intact, even though it is a large molecule with molecular weight ranging from 5,000-50,000 daltons. The lower molecular weight chondroitin (less than 16,900 daltons) appears to be absorbed intact. When administered, chondroitin exhibits a tropism for GAG-rich tissues such as the eyes, joints, lumbar disks, and epiphysis at the ends of long bones.
Glutathione (reduced = GSH; oxidized = GSSG)
Glutathione is a tripeptide consisting of [gamma]-glutamine-cysteine-glycine, and is the most abundant endogenous non-protein thiol. Functions include detoxification of free radicals and peroxides, regulation of cell growth and protein function, and maintenance of immune function. Glutathione deficiency can be induced by protein-deficient diets that are also low in SAAs. GSH is a substrate for GSH transferases and peroxidases, enzymes that catalyze the reactions for detoxification of xenobiotics and reactive oxygen species.
The glutathione pool is of key importance in the defense against oxygen radical pathology. GSH has a mild sparing effect on vitamins C and E through its role as a reducing agent. Precursors of GSH include cysteine, N-acetylcysteine, glutathione monoethyl ester, and oxothiazolidine 4-carboxylate (OTC). While administration of oral glutathione increases hepatic GSH levels in fasted rats,it is not completely clear whether the increase in GSH is from direct absorption of the oral GSH or because GSH contains cysteine, the key precursor. There are reports (both animal and human), however, of oral GSH being absorbed intact.
Low GSH levels in elderly subjects have been theorized to accelerate the aging process. Therefore, maintaining good GSH status during aging may provide a survival advantage in humans.
There is a relationship between GSH, nutrition, and oxidative stress. In diseases where decreased tissue GSH and increased oxidative stress are implicated, or where there is protein-energy malnutrition seen as a secondary manifestation, such as in AIDS, cancer, burns, chronic digestive diseases, alcoholism, or in primary malnutrition, restoration of GSH through administration of cysteine could be beneficial.
Cysteine plays important roles as an extracellular reducing agent, a critical substrate for protein synthesis, and the rate-limiting precursor to GSH and taurine. Cysteine can be given orally to increase GSH or to chelate trace elements in the gut, thereby decreasing absorption of both cysteine and the trace element. Orally administered cysteine markedly improves growth and reduces liver copper deposition in animals fed high levels of inorganic copper. Excessive copper ingestion impairs SAA utilization and increases the dietary requirement for SAA as well. Cobalt and selenium toxicity can be ameliorated by oral cysteine ingestion. NAC may be a preferred delivery system for cysteine because cysteine readily absorbs moisture and oxidizes; whereas, NAC is more stable and may be better absorbed.
Taurine is a conditionally essential sulfonated beta amino acid derived from methionine and cysteine metabolism. Taurine is present in high concentrations in most tissues, particularly in proinflammatory cells such as polymorphonuclear phagocytes and in the retina. Retinal pathologies have been reported for animals and humans deficient in taurine. With the exception of cow’s milk, taurine is widely distributed in foods from many animal (but not plant) sources.
Metabolic actions of taurine include bile acid conjugation, detoxification, membrane stabilization, osmoregulation, and modulation of cellular calcium levels.Although taurine is synthesized from SAA, concern has been expressed about the adequacy of endogenous sources, especially in neonates. Accordingly, proprietary infant formulas are now supplemented with taurine. Clinically, taurine, which achieves good uptake via oral supplementation, has been used with varying degrees of success in the treatment of the following conditions: cardiovascular diseases, hypercholesterolemia, epilepsy and other seizure disorders, macular degeneration, Alzheimer’s disease, hepatic disorders, alcoholism, and cystic fibrosis.
Alpha Lipoic acid (thioctic acid, ALA)
Alpha-lipoic acid plays an essential role in mitochondrial dehydrogenase reactions and is therapeutically useful for preventing free radical cellular damage, reducing oxidative stress, lowering blood sugar, and enhancing the antioxidant potency of other antioxidants (ascorbate and vitamin E). Working in both aqueous and hydrophobic environments, ALA has also been shown to increase coenzyme Q10 and intracellular GSH levels. After oral administration, ALA is readily absorbed and converts to its reduced form, dihydrolipoic acid (DHLA). Lipoic acid administration has been shown to be beneficial in a number of conditions including ischemia-reperfusion injury, diabetes (hydrophobic binding to protein such as albumin occurs which can prevent glycation reactions), cataract formation, neurodegeneration, and radiation injury.
DMSO (Dimethyl sulfoxide)
DMSO, a by-product of the wood industry, was first introduced as a therapy to the scientific community in 1963 by a research team headed by Stanley W. Jacob, MD. Unlike MSM, DMSO is not found in the diet. DMSO can scavenge [O[H.sup.-]] free radicals, a primary trigger in the inflammatory process, and pass through membranes easily. Additionally, it has been demonstrated that DMSO can exert a protective effect on hyaluronic acid against depolymerization due to insult from [O[H.sup.-]], gamma radiation, or neutrophil degranulation. Neutrophil-mediated depolymerization with associated release of [O[H.sup.-]] is theorized to contribute to the breakdown of joint tissue in inflammatory arthritic conditions.
DMSO’s ability to penetrate tissues varies with its strength. A 70-90 percent DMSO solution has been found to be the most effective strength, with penetration ability actually dropping with concentrations higher than 90 percent. Two topical formulas used by the DMSO clinic (now closed) at Oregon Health Sciences University are listed in Table 3.
DMSO has the potential to drive with it across membranes other drugs or substances. Possible efficacy exists for DMSO in the treatment of: pain, inflammation, arthritis, wound healing, burns, amyloidosis, and interstitial cystitis. The FDA has approved its use for interstitial cystitis. Side effects of DMSO can include contact urticaria, desquamation, burning sensation, and garlic-like breath odor.
Methylsulfonylmethane (MSM, dimethyl sulfone, crystalline or DMSO2)
MSM is found in foods, including fruit, alfalfa, corn, tomatoes, tea, and coffee; in human and bovine milk; and in human urine (4-11 mg/day of MSM are normally excreted in the urine). Easily soluble in water, MSM contains 34-percent elemental sulfur. A normal oxidation product of naturally occurring DMSO, MSM does not cause a garlic-like body odor (like DMSO) when ingested. When DMSO enters the body, approximately 15 percent of it is converted to MSM. Reported uses for MSM in humans include treatment for conditions such as hyperacidity, parasites, constipation, musculoskeletal pain, arthritis, allergies, and for immunomodulation.
There is a metabolic relationship between methionine and MSM. When cows were fed D, L-methionine orally a substantial increase in urinary MSM excretion was observed. Little is known about the pharmacokinetics of MSM in humans. A 1975 study found recovery of MSM administered orally to humans was only three percent, suggesting some type of utilization or modification in the gut or liver. In one case report, using in vivo proton magnetic resonance spectroscopy, MSM was detected in the brain of a normal 62-year-old male taking oral MSM, strongly suggesting that MSM is absorbed and can cross the blood-brain barrier, since MSM is not normally found in the brain. The cerebral spinal fluid of this patient was tested for MSM content to rule this out as a source of MSM. The subject had ingested MSM at a dose of 182 mg/kg for seven days followed by 2,000 mg/day as a maintenance dosage. The concentration of this compound in the brain was measured to be 2.4 mmol, with a washout half-life of approximately 7.5 days.
To determine whether sulfur from MSM is incorporated into SAAs, radio-labeled MSM was administered to guinea pigs and incorporated and methionine and cysteine was measured. One percent of the radioactivity was incorporated into serum methionine and cysteine, none was found in the feces, and most was excreted in the urine. Although this work was done in 1986, a follow-up study has not been performed.
Subjects who showed hypersensitivity to aspirin, oral antibiotics, and other NSAIDS were drug-tolerant when MSM was given with or within an hour of ingesting the sensitizing drug. MSM has been reported to be active in vivo and in vitro against Giardia, Trichomonas, and round worms, where MSM may compete for binding sites at the mucus membrane, blocking interface between host and parasite.
Methylsulfonylmethane is one of the least toxic substances in biology, similar in toxicity to water. The lethal dose (LD50) of DMSO for mice is over 20 g/kg body weight. Since MSM is a metabolite of DMSO, this should be a reflection of MSM toxicity. According to research done at the MSM clinic at the Oregon Health Sciences University, long-term use of MSM at a dose greater than 2 g/day is well tolerated, producing no adverse effects.
In genetically susceptible mice, both MSM and DMSO were shown to be effective in preventing autoimmune disease and inflammatory joint disease. In addition, tumor onset in colon cancer-induced rats was markedly delayed in animals receiving MSM supplementation versus controls, suggesting a chemopreventive effect, Four-percent MSM in drinking water had a similar delaying effect on rat mammary breast cancer. Fewer poorly differentiated tumors were noted in treatment groups. Neither weight loss nor toxicity was observed in animal reports.
In clinical studies, MSM was used for treating six patients with interstitial cystitis. Patients were given 30-50 cc of MSM instilled into the bladder at weekly intervals. Five patients became asymptomatic while one had bladder spasms and withdrew from treatment. This case series used DMSO as well, but it was found that MSM provided better results. In addition to scavenging free radicals and inhibiting growth of vascular smooth muscle cells, MSM has been reported to inhibit cell growth more effectively than DMSO.
Because sulfur is needed for the formation of connective tissue, MSM has been studied for its use in treating arthritis. The concentration of sulfur in arthritic cartilage has been shown to be about one-third the level of normal cartilage. A preliminary study was performed on 16 patients suffering from degenerative arthritis. Ten patients, randomly chosen, were treated with 2,250 mg MSM per day while six patients received placebo capsules. Eight of the ten patients experienced some relief within six weeks, while only one person showed minimal improvement on the placebo.
MSM has also been reported to reduce the duration and need for chiropractic visits necessary for treating athletic injuries. A randomized, placebo-controlled clinical trial (sponsored by a supplier of MSM) was conducted on 24 subjects who had sustained acute injuries. Both groups were treated with routine chiropractic manipulation, ultrasound, and muscle stimulation at each visit. The experimental group received three capsules (the exact dose was not given in the study) per day. Patients were discharged from care when all symptoms had resolved. A 58.3-percent symptom reduction on MSM, versus 33.3-percent reduction on placebo was recorded. Symptom resolution and evaluation consisted of the objective findings of the examining doctors at each visit; patient responses regarding symptoms were graded on a scale from 1-10. Patients on MSM had an average of 3.25 visits, while those on placebo had an average of 5.25 visits (an average of two fewer visits in the MSM group) before reaching a recovery phase.
There is very little information in the peer-reviewed literature on the use of MSM alone in humans; therefore, more human trials are called for to fully assess MSM’s therapeutic benefits.
S-adenosylmethionine is an important methyl donor and metabolite of the sulfur-containing amino acid, methionine. Like methionine, SAMe is involved in numerous metabolic processes in the body that require sulfur. The body typically manufactures all the SAMe it requires from methionine, but a defect in methylation or a deficiency in any of the cofactors required for SAMe production (methionine, choline, folate) is theorized to reduce the body’s ability to produce SAMe.
Methylation defects have been implicated in the etiology of psychiatric illness, and depression is the most common neuropsychiatric complication of a deficiency in the methyl donor, folate. Increasing levels of SAMe through supplementation may act as an effective antidepressant by elevating serotonin and dopamine activity in the brain, SAMe has performed as well as conventional antidepressant drugs in studies of depression, where it has been demonstrated that SAMe can alter mood. SAMe also has a fundamental role, as a methyl group donor, in transmethylation reactions in which membrane phospholipids are synthesized and is mandatory for the maintenance of membrane fluidity.
Another metabolic pathway involving SAMe, trans-sulfuration, is initiated with the release of a methyl group from the molecule and the formation of S-adenosyl-homocysteine, which is first converted to homocysteine, then cysteine, a precursor of glutathione. Experimental investigations suggest the administration of SAMe exerts analgesic effects and stimulates the synthesis of proteoglycans by articular chondrocytes, with minimal or absent side effects on the gastrointestinal tract and other organs. The effect of SAMe in osteoarthritis is similar to that exerted by NSAIDs, but it is better tolerated, NSAIDs, at normal pharmacological concentrations, have been demonstrated to inhibit glycosaminoglycan synthesis in human articular cartilage, in addition to causing gastrointestinal bleeding and renal problems. Because of the side effects associated with NSAID use for rheumatic pain, SAMe could be used as a safe alternative.
In ethanol-fed baboons, SAMe prevents depletion of glutathione levels, normalizes mitochondrial enzymes, and results in histological improvement of hepatic lesions. In healthy human volunteers it was demonstrated that, after ethanol ingestion, SAMe significantly lowered plasma concentration of ethanol and acetaldehyde. In a two-year double-blind study by Mato et al, SAMe was tested in patients with alcoholic cirrhosis. A 47-percent lower rate of death or need for liver transplantation was noted compared to controls. Patients took 1,200 mg SAMe/ day. In people with less severe cirrhosis, the results were even more impressive. SAMe has also been proposed as an alternative to N-acetylcysteine in patients who present late after an overdose of acetaminophen.
Methionine is one of the main sources of sulfur in the body and, although it cannot be synthesized by animals, most non-restrictive Western diets supply adequate amounts. Methionine is necessary for the synthesis of proteins and is an important methyl donor. As a methyl donor methionine helps prevent fatty liver through its ability to transmethylate to form choline, necessary to prevent fatty liver disease and eventual cirrhosis. Human studies indicate methionine can lower acetaldehyde levels after alcohol ingestion. Because acetaldehyde is toxic, methionine may be effective in reducing the damaging effects of alcohol. Patients with AIDS have low levels of methionine, and there are reports of its effectiveness in the treatment of Parkinson’s disease and acute pancreatitis.