NAC is an example of a class of substances known as conditional nutrients. which are a handful of substances which are present in the body, which the enzymes systems of the body can synthesize, which decline progressively with age. The effect of these declining levels is synonymous with the process we call “”aging.”” These items include: glucosamine, co-enzyme Q10, ferulic acid, glutathione, N-acetyl-L-cysteine, and lipoic acid.
NAC is the pre-acetylized form of the simple amino acid Cysteine. N-acetyl-L-cysteine is a powerful antioxidant and a premier antitoxin and immune support substance. Antioxidants neutralize free radicals, which are produced by normal metabolic activity. When free radicals are left unchecked they cause damage to cells and DNA and are considered by scientists to be a major factor in the aging process.
N-acetyl-L-cysteine has been shown to provide protection against free radicals as well as a broad range of toxic hazards such as: acrolein (found in barbecue and cigarette smoke and auto exhaust), bromobenzene, paraquat (a toxic herbicide), overdoses of acetaminophen, and the side-effects of cyclophosphamide and adrimycin (anti-cancer drug).
The key to this protection may be the sulfur and sulfhydryl groups contained in N-Acetyl Cysteine and its derivative, glutathione. Both cysteine and methionine are precursors of glutathione, but N-acetyl-L-cysteine is better. L-cysteine loses approximately 85% of its sulfur group (which becomes the active part of glutathione) in the digestion process, while N-Acetyl-L-cysteine, a more stable compound, loses only 15%. This means that N-Acetyl-L-cysteine has almost six times more effective sulfur groups left after digestion.
N-Acetyl-L-cysteine is also a better source of glutathione than taking glutathione itself, because less than half of supplemental glutathione gets out of the digestive system and into the body. This greater efficiency is important since cellular glutathione levels tend to drop 30% to 35% with age. Supplemental N-acetyl-L-cysteine may have an anti-aging effect by increasing glutathione levels in the liver, lungs, kidneys and bone marrow.
NAC is currently the dietary supplement of choice for building up or conserving the body’s stores of glutathione, cysteine, and other sulfhydryl antioxidant resources. NAC is well tolerated, is well absorbed, resists enzymatic breakdown, and has been proven to raise internal GSH and cysteine levels when taken orally.
NAC has a positive effect in the treatment of AIDS probably through its action of increasing intracellular glutathione levels.
In addition to maintaining intracellular glutathione levels, NAC supplementation has been shown to suppresses Human Immunodeficiency virus (HIV) replication, to be protective against cell damage caused by chemotherapy and radiation therapy, to be immune enhancing, to protect against toxins as acetametaphen and other drugs, mercury, lead, and others, and is mucolytic, that is, it breaks up mucus seen in bronchoulmonary disease as cystic fibrosis, chronic bronchitis, asthma, and pneumonia.
Oxidative stress has emerged in recent years as a suspected component in the pathogenesis of HIV disease. Increasing numbers of researchers agree that even in the earliest stages of infection, a deleterious reductive-oxidative (redox) imbalance may occur, This means that increased damage causing reactive oxygen intermediates (also called “”free radicals””) are generated at the same time that stores of naturally occurring antioxidant reducing agents are depleted. The possible result is the uncontrolled presence of oxygen-containing molecules which may cause damage to cell membranes, proteins and nucleic acids, and alterations in the intra- and inter-cellular environments. The net effect of this damage has been termed oxidative stress.
NAC is essential for the synthesis of glutathione (GSH) in the body. It has been used as a possible treatment for HIV infection for over three years. In the U.S. it is available as the prescription aerosolized drug Mucomyst by Bristol Laboratories, a division of Bristol-Myers and is used to treat acetaminophen (Tylenol) overdose and chronic bronchitis. In Europe where it has been used orally for decades it is marketed under the trade name of Fluimucil by Italy’s Zambon group. The oral European version of NAC is available at buyers’ clubs in the United States.
The rationale for the use of NAC in HIV treatment is based on evidence from in vitro studies that cells deficient in GSH are particularly sensitive to inflammatory cytokines (tumor necrosis factor alpha). Elevated levels of TNF are known to activate and increase replication. That is when TNF stimulates the nuclear transcription factor kB (NF-kB) in HIV-infected cells, virus transcription and replication is greatly increased. By increasing the levels of intracellular GSH, proponents of NAC therapy hope to offset TNF-mediated HIV replication. GSH is present in almost all human tissues. It is critical for a number of important cellular functions. Of primary importance, however, is its vital role as the principal intracellular defense against oxidation by free radicals and their compounds. In their 1992 review article Staal et al reported that “”adequate levels of GSH are required for mixed lymphocyte reactions, T-cell proliferation, T and B cell differentiation, cytotoxic T-cell activity, and natural killer cell activity. Decreasing GSH by 10 to 40 percent can inhibit completely T-cell activation in vitro. Thus, an intracellular GSH deficiency in lymphocytes has profound effects on immune functions.””
Staal et al, among others, advocate for the use of NAC as a therapeutic agent in AIDS. The reasons they state: “”NAC has antiretroviral effects in vitro, low toxicity in vivo, a long history of use in patients, can be given orally in a palatable form and is inexpensive.””
Antioxidants neutralize free radicals, which are produced by normal metabolic activity. When free radicals are left unchecked they cause damage to cells and DNA and are considered by scientists to be a major factor in the aging process. NAC is a more stable form of L-Cysteine because it has an acetyl group (CH3CO) attached. NAC has all the properties of L-Cysteine but is more water soluble and said to be more bioavailable than L-Cysteine.
It is known & marketed as an “”anti-amalgam”” medicine, because it helps remove (chelate) mercury from the body. It also generally improves the bodys immune system, making it better able to fight off disease. It is freely available from health-food shops in many countries. NAC has neither a sedative or stimulant effect, and is a safe substance showing excellent tolerance in patients.
Free radical mediated mechanisms have been suggested as contributing to the development of several neurodegenerative diseases. Our initial emphasis was the treatment of hereditary movement disorders, particularly the hereditary ataxias. More recently, patients with other neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and Alzheimer’s disease have been treated with NAC. We report here results of studies with NAC
Treatment with high dose NAC has produced modest improvement in several patients with neurodegenerative disorders. Where improvement has been noted, it has usually been early in treatment and then tends to plateau. Some patients have not seen an initial improvement but remain on NAC as a possible means to prevent further progression of their disorder. In some 40 patients tested (including patients with HSCA, AT, FA, ALS, MS, DN and HC) pretreatment FRESA analysis indicated an imbalance in antioxidant enzyme activity. Although a few patients claimed some benefit from more traditional antioxidant therapies (e.g vitamins A,C,E,B2, and selenium), most patients said these were without noticeable benefit. As suggested, improvement in physical condition may correlate with improved free radical status. This suggests that these enzyme abnormalities are not primary in these disorders but occur secondary to whatever gene defects trigger excess free radical activity (e.g., GSHpx and SOD are readily destroyed by excess superoxide). This study indicates the possibility that if improvement in the antioxidant status occurs, the potential exists for arresting progression of the disease and in some cases an improvement in patient condition.
The high level of safety and variety of antioxidant actions of NAC suggest it as a very promising new tool for treatment of neurodegenerative disorders. In recent months, scientific reports of animal and in-vitro studies indicate that NAC inhibits neuronal apoptosis and toxicity in models of multiple sclerosis, amyotrophic lateral sclerosis and diabetic necrosis.
The most commonly used chemopreventive agents in the prevention of oral leukoplakia, head and neck cancer, and lung cancer are beta-carotene, vitamin A, and other retinoids. One of the few chemopreventive agents not in this group and presently being used in a clinical trial is N-acetyl-l-cysteine (NAC). NAC, an antioxidant, is used in EUROSCAN, a European Organization of Research and Treatment of Cancer (EORTC) chemoprevention study in curatively treated patients with oral, laryngeal, or lung cancer. The rationale for choosing NAC is based on a variety of experimental data showing its ability to exert protective effects, including extracellular inhibition of mutagenic agents from exogenous and endogenous sources, inhibition of genotoxicity of reactive oxygen species, modulation of metabolism coordinated with blocking of reactive metabolites, protection of DNA and nuclear enzymes, and prevention of the formation of carcinogen-DNA adducts. NAC has also demonstrated an effect on mutagen-induced chromosomal sensitivity assays, and on anticarcinogenicity in experimental animal models. In addition, preliminary data from EUROSCAN show good compliance in treated patients and a low frequency of side effects.
The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striynergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials.
As mentioned above NAC is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. N-acetyl-L-cysteine (NAC) protects cells against death induced by exposure to noxious stimuli and against programed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors. NAC prevented glutamate-induced death of oligodendrocytes and tumor necrosis factor a(TNF-a)-induced death of oligodendrocytes and L929 fibroblasts. Moreover, suboptimal doses of NAC plus ciliary neurotrophic factor (which also protects oligodendrocytes against TNF-a-mediated killing) acted synergistically to protect oligodendrocytes against TNF-a-induced death. In all paradigms, NAC was either equally or more effective than the other compounds examined. In light of the long history of therapeutic application of NAC, we suggest that use of this compound may be of interest in conditions where certain toxin-mediated forms of cell death and/or apoptosis contribute significantly to disease.
* Carole Lemens, Craig Sterrit. Antioxidants, Oxidative Stress, and NAC. From Project Inform. For more information, contact the National HIV/AIDS Treatment Hotline, 800-822-7422, or visit our website, www.projectinform.org
* Staal FJ, Ela SW, Roederer M, Anderson MT, Herzenberg LA, Herzenberg LA. Glutathione deficiency and human immunodeficiency virus infection. Lancet,1992;339(8798):909-912.
* B.J.Wilder, M.D., Russell W. Hurd, M.S., Et al. Treatment of neurodegenerative disease with N-Acetylcysteine. Department of Neurology and Brain Institute, University of Florida, Gainesville, FL 32610
* De Vries N, De Flora S. N-acetyl-l-cysteine. J Cell Biochem Suppl 17F:270-277; 1993.
* De Flora S. D’Agostini F. Et al. Institute of Hygiene and Preventive Medicine, University of Genoa, Italy. Int J Cancer (UNITED STATES) Sep 17 1996, 67 (6) p842-8
OTHER REFERENCES:
NAC supplement for brain damage in boys – Nutra USA, 5/4/04 – “”Because it enhances the production of the enzyme glutathione, NAC is thought to both stave off disease and play an important role in boosting the immune system””
Antioxidant may prevent destruction of delicate hairs in inner ear – HealthDay, 12/26/03 – “”The drug is N-acetylcystine (NAC). It is an antioxidant compound that loosens mucus in airways and treats liver damage from overuse of acetaminophen. But research has shown it might also help prevent noise-induced hearing loss””
N-Acetylcysteine Beneficial for Chronic Lung Disease – Healthwell Exchange Daily News, 10/2/03
Pre-treatment With Acetylcysteine For Cardiac Catheterisation Reduces Contrast-Induced Nephropathy – Doctor’s Guide, 12/5/03
Thiol-Containing Antioxidant Shows Promise in Preventing Contrast Nephropathy – Doctor’s Guide, 8/25/03 – “”Treatment with acetylcysteine, a thiol-containing antioxidant, shows promise in preventing contrast nephropathy in patients with chronic renal insufficiency””
High Cysteine Levels Linked to Lower Rates of Breast Cancer – Doctor’s Guide, 7/15/03 – “”Women in the highest quintile for measured cysteine levels in this study had a 56% lower risk of invasive or in situ breast cancer than women in the lowest quintile … The findings were more pronounced when only invasive cancer was considered … Cysteine or its precursors might have the potential to be chemoprotective against breast cancer””
Black Cohosh, Cysteine Studied in Breast Cancer – Health Supplement Retailer, 7/14/03
N-Acetyl Cysteine Prevents Kidney Damage from Coronary Procedure – New Hope Natural Media, 5/1/03 – “”Up to 15% of people undergoing coronary angiography may experience kidney damage from the contrast dye … randomly assigned to receive either 600 mg of oral NAC twice a day on the day before and the day of the procedure or a similar looking placebo … Only 4% of those taking NAC, compared with 12% of those taking the placebo, experienced a 25% increase in blood creatinine within 48 hours of receiving the contrast dye””
Cardiovascular End Points Reduced With Antioxidant Acetylcysteine In Haemodialysis Patients – Doctor’s Guide, 2/28/03 – “”They were assigned to receive either acetylcysteine 600 mg twice daily or a placebo … Primary end point was a composite variable composed of cardiac events that included fatal and non-fatal myocardial infarction, death from cardiovascular disease, necessity for either coronary angioplasty or by-pass surgery, ischaemic stroke, peripheral vascular disease requiring amputation or need for angioplasty … A primary end point was established in 18 of the 64 [28%] haemodialysed patients who received acetylcysteine, and 33 of 70 [47%] patients undergoing haemodialysis assigned to the control group
N-Acetyl Cysteine Improves Insulin Resistance in Women with Polycystic Ovary Syndrome – New Hope Natural Media, 12/12/02 – “”PCOS … affects up to 10% of all women of reproductive age … characterized by enlargement of the ovaries, irregular menstrual cycle, failure to ovulate, obesity, high levels of insulin in the blood and insulin resistance, excessive hair growth (due to increased testosterone) and infertility. More than 50% of all women with PCOS have high insulin levels, which may be a risk factor for diabetes, high blood pressure, blood clots and heart disease … Women with high initial insulin levels who took NAC had a significant reduction in insulin levels following the glucose tolerance test and also showed improved insulin sensitivity””
Acetylcysteine Can Reduce Cardiovascular Events in Patients with Endstage Renal Disease – Doctor’s Guide, 10/1/02 – “”therapy with acetylcysteine appears to significantly reduce cardiovascular events among haemodialysis patients””
N-Acetylcysteine Helpful for Eye Disorder – New Hope Natural Media, 9/26/02
Getting More Glutathione? – Dr. Weil, 8/29/02 – “”To my knowledge, the only supplement that effectively raises glutathione levels in the body is N-acetyl-L-cysteine (NAC). My colleague Kathleen Johnson, a dietician here at the Program in Integrative Medicine, tells me that other glutathione supplements are ineffective because they?re digested before they can get into the bloodstream””
Putting Antioxidants To Use In Functional Formulas – Functional Foods & Nutraceuticals, 5/02 – “”N-acetylcysteine (NAC), like alpha-lipoic acid, is a potential antioxidant and precursor to glutathione. However, NAC is also a powerful immune stimulant. For example, an Italian study of 262 elderly subjects found that 600mg NAC, taken twice daily, reduced flu symptoms by two-thirds.18 Large dosages of NAC?up to several grams daily?can extend the life expectancy of patients with AIDS,19 and some research suggests that it may also reduce the risk of cancer””
Acetylcysteine Prevents Renal Problems After Angiography – Doctor’s Guide, 3/18/02 – “”Changes in creatinine mean values after 48 hours were -0.4 (ñ0.3) and +0.1 (ñ0.3) mg/dL for treatment and control groups, respectively (p<0.001). The benefit was larger in patients with baseline creatinine levels higher than 2 mg/dL, at -0.4 (ñ0.4) compared to +0.5 (ñ0.3) mg/dL (p<0.001)””
Antioxidant Boosts Cognitive Function In Alzheimer’s Patients – Intelihealth, 11/15/01 – “”the antioxidant N-acetylcysteine (NAC) may improve certain cognitive skills in people with Alzheimer’s disease … Although participants in the NAC group did not outperform placebo patients in day-to-day activities, they did fare significantly better than the placebo group on certain cognitive tests””
N-acetylcysteine Improves Blood Vessels – Nutrition Science News, 5/01 – “”Researchers suspect this is because NAC enhances the bioavailability of the relaxing substance nitric oxide, but because nitric oxide has a short half-life and cannot be measured by current methodology, they were unable to determine this directly. In addition, NAC may act as an antioxidant that protects nitric oxide destruction””
Glutathione: The Eye Healer Within – Nutrition Science News, 4/01 – “”Supplementing with glutathione to boost glutathione levels is not well understood. Glutathione is a large molecule that is not easily absorbed, but it is a tripeptide with cysteine?a sulfur-bearing amino acid?in the middle. As cysteine is broken down in the digestive tract, its sulfur is absorbed and utilized to make more glutathione””
Diabetologia. 1998 Nov;41(11):1392-6.
Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes.
De Mattia G, Bravi MC, Laurenti O, Cassone-Faldetta M, Proietti A, De Luca O, Armiento A, Ferri C.
Universita La Sapienza, Fondazione Andrea Cesalpino, Roma, Italy.
To assess in vivo effects of antioxidants on vascular cell adhesion molecule (VCAM)-1 expression, circulating soluble VCAM-1 and intraerythrocytic reduced glutathione (GSH) and GSH disulphide (GSSG) concentrations were evaluated in non-insulin-dependent diabetic patients without complications (9 men, 6 women, 48 +/- 6 years old) before and after 1 month of either oral N-acetyl-L-cysteine (1.200 mg/day) or placebo treatments, given in randomized, cross-over, double-blind fashion. Ten healthy subjects (7 men, 3 women, 52 +/- 4 years old) served as control subjects. Baseline plasma VCAM-1 concentrations were higher (p = 0.007) in non-insulin-dependent diabetic patients (707.9 +/- 52.5 ng/ml) than in control subjects (627.3 +/- 84.6 ng/ml). Intraerythrocytic GSSG content was higher (non-insulin dependent diabetic patients: 0.618 +/- 0.185 micromol/g Hb; control subjects: 0.352 +/- 0.04 micromol/g Hb, p = 0.0002), whereas intraerythrocytic GSH concentrations were lower (p = 0.001) in non-insulin dependent diabetic patients (6.0 +/- 0.7 micromol/g Hb) than in control subjects (7.1 +/- 0.5 micromol/g Hb). The mean GSH:GSSG ratio was also lower (p = 0.0001) in the first (10.9 +/- 4.5) than in the second group (20.2 +/- 1.4). Circulating VCAM-1 and intraerythrocytic GSH concentrations were negatively correlated in non-insulin diabetic patients (r = 0.605, p = 0.01). Treatment with N-acetyl-L-cysteine decreased plasma VCAM-1 (p = 0.01) and intraerythrocytic GSSG (p = 0.006) but increased GSH concentrations (p = 0.04) and the GSH:GSSG ratio (p = 0.004) in non-insulin dependent diabetic patients. Our data indicate that the vascular endothelium is activated in non-insulin dependent diabetes. Antioxidant treatment counterbalanced such endothelial activation. Thus, antioxidant agents might protect against oxidant-related upregulation of endothelial adhesion molecules and slow down the progression of vascular damage in non-insulin dependent diabetes.