Most people are accustomed to thinking of antioxidants as vitamins and minerals. But there are many other natural substances that function in this way. Glutathione, a powerful antioxidant enzyme produced in our bodies, is one such substance. N-acetylcysteine (NAC), an amino acid required by our bodies to produce glutathione, appears to possess particular antioxidant properties, as well. See AMINO ACIDS
FUNCTIONS AND USES
As antioxidants, these two related substances are intimately involved in the detoxification process, and are important members of our defenses against environmental toxins and carcinogens. They also protect our cells from oxidative stress-damage that may occur from a variety of environmental insults. Because such damage plays a role in degenerative diseases and in the weakening of the immune system, it should come as no surprise that it is the degenerative diseases-cancer, cardiovascular disease, and arthritis, for instance and viral infections that respond to glutathione and NAC supplementation. In general, the studies of NAC have focused on its use in the treatment of viral infections, while the studies of glutathione have concerned the treatment of cancer. However, there is considerable overlap in the function and use of these two antioxidants, and it is reasonable to assume that both work for many conditions.
Infection and Immunity
As already mentioned, most studies of NAC have focused on its potential use as an antiviral agent, specifically in the treatment of HIV (human immunodeficiency virus) infection and AIDS (acquired immune deficiency syndrome). Studies have sh0 Tathat NAC reduces the replication of HIV. Moreover, when NAC is given along with vitamin C and glutathione, the results have been more striking than when any of these substances is given alone. Other studies have suggested that NAC and glutathione may work together to extend the latency period of HIV, delaying the onset of opportunistic infections. Researchers have also suggested that glutathione supplementation, along with NAC, inhibits expression of HIV-meaning that although a person may test positive for HIV, he or she may otherwise show no evidence of the infection. These findings may offer a promising new means of interfering with the progression of this disease.
Several researchers have indicated that NAC and glutathione are both natural nontoxic anti-HIV agents, and that they may inhibit the replication of other viruses, as well. Reports at the Ninth International Conference on AIDS in Berlin suggested that NAC could actually prevent apoptosis, a process that programs cell death. This may have important implications, as in HIV infection; apoptosis is a permanent and chronic situation.
In both animal and human studies, both NAC and glutathione have been shown to help protect against damage to the immune system. Indeed, deficiencies of these antioxidants may result in depletion of many types of immune cells, including macrophages, phagocytes, and T-cells. Supplementation, on the other hand, has been shown to improve immune function. In addition, supplementation with glutathione has been shown to increase the activity of neutrophils, another type of immune cell.
In preliminary animal and cell culture studies, glutathione has shown promise as a natural cancer preventive and therapeutic agent. Studies on glutathione have suggested that it may be particularly useful in some cancer patients receiving chemotherapy. For example, in one study, intravenous glutathione was shown to protect against kidney damage induced by the medication cisplatin. Interestingly, the survival rates of ovarian cancer patients receiving both glutathione and cisplatin in the early, middle, and late stages of the disease, were extraordinarily high compared with the rates of those receiving cisplatin alone. Based on these results, the authors of the study concluded that this combination represents a promising approach to optimizing the clinical use of cisplatin in the treatment of ovarian cancer. In another study, high doses of glutathione appeared to improve survival in women with liver cancer. In animals, it prevented chemotherapy-induced hair loss when administered intravenously or applied topically.
Numerous studies have demonstrated NAC’s ability to protect against toxic substances. It has a long history of both oral and intravenous use as an antidote for acetaminophen (Tylenol) toxicity, which can result in liver necrosis (cell death). NAC has also been shown to be an antidote for carbon tetrachloride exposure, protecting against both liver and kidney damage. Workers at risk for exposure to this toxic and carcinogenic chemical include air transportation workers, automobile mechanics, dry cleaning workers, grain workers, hazardous waste workers, museum workers, pesticide applicators, pharmaceutical manufacturers, steel mill and blast furnace workers, telephone and telegraph equipment and manufacturing workers, and tin waste-recovery workers. Possibly as the result of environmental toxins in general, several studies have shown that sperm counts and motility have dropped by half all over the world. Glutathione may help reverse this trend, as infertile men who received glutathione injections have experienced a significant increase in the motility of their sperm, and a significant reduction in atypical sperm.
As antioxidants, both glutathione and NAC show great promise as a means of protecting against many of the disorders associated with aging. Indeed, studies of large segments of the elderly population have shown low glutathione levels. Already-completed research show that glutathione and NAC may help stave off the ravages of aging in the eye, the heart, and the nervous system. Specifically, glutathione is known to defend the eye against degeneration by protecting the lens and the macula, a part of the retina, against oxidative stress. Thus, glutathione-as well as NAC, because it replenishes glutathione-may be useful in the prevention of both cataracts, the clouding of the lens of the eye, and macular degeneration, a condition that can eventually lead to blindness.
NAC appears to also be useful in the prevention and treatment of cardiovascular disorders. First, NAC has been shown to lower levels of lipoprotein(a). This is a significant finding, because high levels of lipoprotein(a) have been correlated with an increased risk of cardiovascular disease. In addition, antioxidants including the enzyme glutathione peroxidase, of which glutathione is a component, NAC, and superoxide dismutase (SOD) seem to reduce the oxidative stress that contributes to the surgical complications associated with cardiopulmonary bypass procedures.
Mucomyst, an inhalant form of NAC, has long been used to manage bronchitis, asthma, and other lung disorders. NAC treats these diseases by breaking up mucus. In addition, NAC can help reduce the high levels of oxidative stress that these disorders can cause in the lung tissues.
Studies have revealed that the brains of Parkinson’s sufferers have reduced levels of glutathione. This deficiency may result in increased oxidative stress, which may then damage the mitochondria, which are tiny powerhouses in the cells that produce energy. By preserving glutathione levels in patients with Parkinson’s, we may be able to prevent, slow, or stop the progression of this disease.
RDIs AND DEFICIENCY SYMPTOMS
There are no established RDIs for glutathione and NAC, and no deficiency symptoms have been identified.
Food Sources: Fresh whole fruits; vegetables; and just-cooked animal foods, including beef, chicken, and fish, appear to be the best sources of glutathione. Dairy foods and grains are poor sources of this substance, and processing and preservation, except for freezing generally cause significant losses of glutathione in foods.
N-acetylcysteine is made from cysteine, an amino acid found in high-protein foods. Thus, the best sources of this substance are eggs, dairy products, fish, poultry, and meat.
Separate supplements are available as glutathione and N-acetylcysteine. Cysteine, the precursor of NAC, is also available in supplement form, but the NAC form appears to be more active. Although perfectly safe, NAC and glutathione are quite expensive. Therefore, most professionals reserve their use for individuals whose health is severely compromised.
NOTE: Glutathione and NAC are found in most Biotics Research Corp.’s Multi?formulas.
OPTIMUM DAILY INTAKE-ODI
There is no Optimum Daily Intake for either glutathione or N-acetylcysteine. However, researchers and practitioners generally use 1 to 3 grams of NAC, and 500 to 1,500 milligrams of glutathione per day.
Remember: If you have a medical condition, please consult with your physician before taking supplements.
TOXICITY AND ADVERSE EFFECTS
There is no known toxicity for either glutathione or NAC when administered orally, although some gastrointestinal effects may occur at high doses. Although shown to be safe, intravenous and inhalant use should be supervised by a physician.
N-acetylcysteine (NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced glutathione (GSH). Histori-cally it has been used as a mucolytic agent in chronic respiratory illnesses as well as an antidote for hepatotoxicity due to acetaminophen overdose. More recently, animal and human studies of NAC have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterized by free radical, oxidant damage. NAC has also been shown to be of some value in treating Sjogren’s syndrome, smoking cessation, influenza, hepatitis C, and myoclonus epilepsy.
Chemistry and Pharmacokinetics
NAC is a sulfhydryl-containing compound that is rapidly absorbed into various tissues following an oral dose, is deacetylated and metabolized in the intestines and liver, and incorporated into disulfide protein peptides. Peak plasma levels of NAC occur approximately one hour after an oral dose and at 12 hours post-dose it is undetectable in plasma. Despite a relatively low bioavailability of only four to ten percent, oral administration of NAC appears to be clinically effective. The biological activity of NAC is attributed to its sulfhydryl group, while its acetyl substituted amino group affords it protection against oxidative and metabolic processes.
Mechanisms of Action
NAC’s effectiveness is primarily attributed to its ability to reduce extracellular cystine to cysteine, or to act intracellularly as a source of sulfhydryl groups. As a source of sulfhydryl groups, NAC stimulates glutathione (GSH) synthesis, enhances glutathione-S-transferase activity, promotes liver dminoification by inhibiting xenobiotic biotransformation, and is a powerful nucleophile capable of scavenging free radicals. NAC’s effectiveness as a mucolytic agent results from its sulfhydryl group interacting with disulfide bonds in mucoprotein, with the mucus subsequently being broken into smaller, less viscous units. NAC may also act as an expectorant by stimulating both ciliary action and the gastro-pulmonary vagal reflex, thereby clearing the mucus from the airways. Studies have also shown NAC to be of benefit in heart disease by lowering homocysteine and lipoprotein(a) levels via dissociation of disulfide bonds, protecting against ischemic and reperfusion damage via replenishment of the glutathione redox system. as well as potentiating the activity of nitroglycerin.
Several animal and human studies have explored NAC’s effectiveness as a therapeutic agent for various types of respiratory illness. While results varied, NAC administration resulted in decreased expectoration difficulty, cough severity,” and diaphragm fatigue. A small study was conducted with 18 patients diagnosed with fibrosing alveolitis; a condition characterized by severe oxidative stress and decreased glutathione levels. NAC was administered at a dose of 600 mg three times daily for 12 weeks and improvement in both pulmonary function and glutathione levels was noted. In contrast, studies of patients with chronic bronchitis, severe airway obstruction, and cystic fibrosis showed a slight, although not statistically significant, decrease in the exacerbation rate.
Human immunodeficiency virus (HIV)-positive individuals usually exhibit low GSH and cysteine levels, prompting studies on NAC’s effectiveness as a therapeutic tool for these patients. Research suggests that NAC is capable of enhancing T cell immunity by stimulating T cell colony formation, 16 and blocking NF kappa B expression. In a double-blind, placebo-controlled trial Akerlund et al found NAC to positively impact both plasma cysteine levels and CD4+ lymphocyte cell counts. More studies are needed but it appears that if given to HIV-positive patients early in the course of disease, NAC may help to prevent progression to AIDS.
Research has shown NAC to have potential both as a chemopreventative agent and a treatment in certain types of cancer, including lung, skin, head and neck, mammary, and liver cancer. In Vitro studies have demonstrated NAC to be directly anti-mutagenic and anti-carcinogenic as well as inhibit-ing the mutagenicity of certain compounds in vivo. Research also indicates NAC administration in both cell cultures and animal studies selectively protects normal cells, but not malignant ones, from chemotherapy and radiation toxicity. Other in vitro studies noted NAC’s effectiveness at inhibiting cell growth and proliferation in human melanoma, prostate, and astrocytoma cell lines.
Acetaminophen and Other Poisonings
Historically the most prevalent and well-accepted use of NAC has been as an antidote for acetaminophen (Tylenol, paracetamol) poisoning. The resultant liver toxicity is due to an acetaminophen metabolite that depletes the hepatocytes of glutathione and causes hepatocellular damage and possibly even death. NAC administered intravenously or orally within 24 hours of overdose is effective at preventing liver toxicity; however, improvement is most notable if treatment is initiated within 8-10 hours of acetaminophen overdose. NAC’s effectiveness declines when treatment is delayed beyond 10 hours and risk of mortality significantly increases. NAC has also been effective for heavy metal poisoning by gold, silver, copper, mercury, lead, and arsenic, as well as in cases of poisoning by carbon tetrachloride, acrylonitriles, halothane, paraquat, acetaldehyde, coumarin, and interferon. Studies involving these poisons are primarily animal studies or single case reports and therefore additional studies are needed to establish NAC’s effectiveness in this area.
Several small clinical studies have demonstrated that NAC may be an effective therapeutic agent in the management of heart disease. Wiklund et al demonstrated NAC’s ability to reduce plasma homocysteine levels by 45 percent,’while Gavish and Breslow demonstrated NAC (2-4 grams daily for eight weeks) was able to reduce lipoprotein(a) by 70 percent. Due to its ability to significantly increase tissue GSH, NAC may also be useful in treating the ischemia and reperfusion seen in acute myocardial infarction, and the resultant depletion in cellular sulfhydryl groups.’ In addition, NAC appears to potentiate nitroglycerin’s coronary dilating and anti-platelet properties and therefore may be a useful combination therapy in-patients with unstable angina pectoris and myocardial infarction.
Other Clinical Indications
Clinical studies have also demonstrated NAC’s therapeutic benefit in the treatment of Sjogren’s syndrome,” myoclonus epilepsy, influenza,” illness associated with cigarette smoking and hepatitis C.
Safety and Side-Effects
NAC is generally safe and well tolerated even at high doses. The most common side-effects associated with high oral doses are nausea, vomiting, and other gastrointestinal disturbances, and therefore oral administration is contraindicated in persons with active peptic ulcer. Infrequently, anaphylactic reactions due to histamine release occur and can consist of rash, pruritis, angioedema, bronchospasm, tachycardia and changes in blood pressure. Intravenous administration has, in rare instances, caused allergic reactions but they are generally in the form of rash or angioedema. NAC is “Ames test” negative but animal studies on embryotoxicity are equivocal. In addition, studies in pregnant women are inadequate so NAC administration during pregnancy should be with caution and only if clearly indicated. Oral administration of NAC and charcoal at the same time is not recommended, as charcoal may cause a reduction in the absorption of NAC. In addition, as with any single antioxidant nutrient, NAC at therapeutic doses (even as low as 1.2 grams daily), has the potential to have pro-oxidant activity and is not recommended at these doses in the absence of significant oxidative stress.
The typical oral dose for NAC as a mucolytic agent and for most other clinical indications is 600-1500 mg NAC daily in three divided doses. In patients with cancer or heart disease the therapeutic dosage is higher, usually in the range of two to four grams daily. For acetaminophen poisoning, NAC is usually administered orally with a loading dose of 140 mg/kg and 17 subsequent doses of 70 mg/kg every four hours. In acetaminophen poisoning, it is important to begin administering NAC within 8 – 10 hours of overdose to ensure effectiveness.
Alternative Medicine Review, Vol.5, No.5, 2000; P-467-471.
Altern Med Rev 1998 Apr;3(2):114-27
Clinical applications of N-acetylcysteine.
Alternative Medicine Review, Greenwich, CT.
N-acetylcysteine (NAC), the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in aof piety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased GSH or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking. An 18-dose oral course of NAC is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine also appears to have some clinical usefulness as a chelating agent in the treatment of acute heavy metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention to enhance elimination of the metals.
Chest 1995 May;107(5):1437-41
N-acetylcysteine for lung cancer prevention.
van Zandwijk N
Department of Chest Oncology, The Netherlands, Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam.
Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well recognized causes. Apart from oxidants, cigarette smoke contains several precarcinogens, and it is surprising that not every heavy smoker becomes a victim of malignant disease. This points to the interindividual variability in susceptibility to carcinogens and there are several lines of evidence that metabolic factors are involved in such variability. Metabolism of carcinogens and also the subsequent multisteps of carcinogenesis are affected by host factors and governed by the balance between opposite forces, such as metabolic activation and detoxification, formation, and scavenging of radicals and DNA damage and repair. This implies that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione plays a crucial role in the detoxification of xenobiotics. N-acetylcysteine (NAC), an aminothiol and precursor of intracellular cysteine and glutathione, has been shown not only to be an efficient antidote in acetaminophen poisoning but also to possess important chemopreventive properties. In this article, sites and mechanisms of the therapeutic action of NAC are reviewed with special reference to its chemopreventive characteristics.
Respiration 1986;50 Suppl 1:26-30
Acetylcysteine: a drug with an interesting past and a fascinating future.
N-acetylcysteine (NAC) possesses a free sulfhydryl group that can rupture disulfide bridges. Although it is considered to be a mucolytic, its mucokinetic actions include expectorant, bronchorrheic and mucoregulatory contributions. New uses include the management of acetaminophen poisoning and the scavenging of free radicals liberated by cancer chemotherapy drugs. The antioxidant effects may be of prophylactic value in lungs at risk from smoking, pollution and infection. Other uses proposed for NAC include the therapy of connective tissue diseases and its use as a component in life extension diets.
J Cell Biochem Suppl 1995;22:24-32
N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer.
van Zandwijk N
Department of Chest Oncology, HET Nederlands Kanker Institute, Amsterdam, The Netherlands.
Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre) carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi) steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.