N-Acetyl-Cysteine (NAC)

N-acetyl-L-cysteine (NAC) is commonly administered as an antidote against acetaminophen (paracetamol) intoxication and is the preferred agent in the treatment of pulmonary diseases. It is furthermore commonly considered that it restrains human immuodeficiency virus (HIV) replication by scavenging reactive oxygen intermediates (ROI) and thus suppressing activation of nuclear factor kappa B (NF kappa B). We Show here that NAC is in addition able to inhibit hepatitis B virus (HBV) replication, but by a mechanism independent of the intracellular level of reactive oxygen intermediates. Treatment of HBV-producing cell lines with NAC resulted in an at least 50-fold reduction of viral DNA in the tissue culture supernatant within 48 h. This decrease of viral DNA and thus of virions in the tissue culture supernatant is caused by a disturbance of the virus assembly, rather than by a reduction of viral transcripts. Our data strongly suggest a potential use of this well-established, non-toxic drug for the treatment of HBV infection. Since NAC, in contrast to interferon, exerts its anti-HBV activity at a post transcriptional level, a combination of NAC with the established interferon therapy could also be considered.

Other preliminary studies indicate that NAC may improve the response rate when taken in conjunction with interferon. NAC is commonly available from health food stores.

NAC has been used safely at very high doses but side effects have been reported including: stomach upset and diarrhoea. NAC can reduce mucous secretions in the stomach so people with a history of ulcers need to be more cautious if taking NAC The Martindale Extra Pharmacopoeia reports that some antibiotics, including amphotericin, ampicillin, erythromycin and tetracycline may be incompatible or inactivated when mixed with NAC.

It has also been reported that NAC can reduce the absorption of minerals and some nutritionists advocate taking supplements.

Note: Although this article refers to Hepatitis C I have included it here for information:-

Journal of Interferon Research 13:279-282 (1993)..Beloqui, Prieto, et al

Abstract: Hepatitis C virus (HCV) is an RNA virus that replicates in both the liver and lymphoid cells. Interferon-alpha (IFN) is a useful treatment of chronic HCV although resistance to this drug occurs frequently. <snip> In IFN-unresponsive patients, the addition of 600 mg tid of oral N-acetyl cysteine (NAC), a glutathione precursor, resulted in a steady decrease of ALT values in all patients, with complete normalisation in 41% of cases after 5-6 months of combined therapy. <snip> HCV replication was markedly inhibited in lymphocytes and viremia was cleared in one of the 8 patients tested. In conclusion, NAC enhanced the response to INF in CHC. Controlled studies are needed to ascertain whether antioxidant therapy might act in synergy with IFN in chronic viral hepatitis.

This article first appeared in the April, May, June 1994 issues of VRP's Nutritional News

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No information in this article should be taken as a recommendation. If you have any questions about the relationship between N-Acetyl Carnitine and your health, seek the advice of a qualified physician.

A.S. Gissen

Part 1

In 1963 it was demonstrated that N-Acetyl Cysteine (NAC), an endogenous product of cysteine metabolism, could be used as a mucolytic.(1) This had great potential in chronic lung diseases, and NAC quickly became utilized in clinical practice, predominantly in Europe. Since it was believed that NAC, due to its sulfhydryl group, liquefied mucus by directly reducing disulfide bonds in the mucus, NAC was initially given only by inhalation. Subsequently, NAC was also utilised orally, for this mode of administration was also shown to be effective. In the years following the discovery of its mucolytic property, research has shown that NAC is a very effective precursor and stimulator of glutathione synthesis. In fact, NAC's effects on lung disorders and mucus viscosity now appear to be explained by its ability to augment glutathione production, rather than the initial belief that NAC acted directly to break-up mucus.(2) Glutathione is a cysteine-containing tripeptide whose cellular functions include participation in numerous enzymatic reactions; transport of amino acids; and defence from free radicals, reactive oxygen intermediates, and certain toxic chemicals. Because glutathione is an important endogenous antioxidant, NAC has emerged from its mucolytic role to become a potent protective agent in many free-radical mediated conditions and diseases. Indeed, NAC has become a better researched, more effective, and safer antioxidant alternative to L-cysteine. This is because NAC is not only less toxic than L-cysteine, it is much more effective in raising glutathione levels.(3)

N-Acetyl Cysteine Metabolism NAC is quickly absorbed after oral administration, with peak blood levels being obtained within one hour.(4) NAC is rapidly and extensively metabolized in the gut wall and liver, resulting in low blood levels of the parent compound, NAC. One of the major metabolic pathways of NAC metabolism is the conversion of NAC to L-cysteine, and ultimately, the incorporation of cysteine into glutathione. NAC administration has been shown to increase glutathione levels in different tissues of the body, both in animals and humans.(5) L- cysteine, on the other hand, is much less effective than NAC at raising glutathione levels. This is because the administration of L-cysteine results in its rapid oxidation to L-cystine, its insoluble disulfide. NAC's greater effectiveness stems from the preferential incorporation of NAC-derived L-cysteine into glutathione, rather than its oxidation to cystine or metabolism to sulfate or taurine. The majority of L-cysteine metabolism is into pathways that lead to metabolites other than glutathione, while most of NAC metabolism can be accounted for by glutathione synthesis.(6) This preferential distribution of NAC to glutathione represents a novel means of augmenting glutathione production, although the exact mechanism that makes this possible remains the subject of scientific research.

NAC and Oxidation The antioxidant role of NAC, and the glutathione formed from it, first became apparent when it was discovered that NAC could be used for the treatment of acetaminophen poisoning.(7) Acetaminophen is a commonly used analgesic that most of us have used at one time or another. Although very safe when used at therapeutic doses, ingestion of 10- 15 grams of acetaminophen in a single dose can result in liver damage 2-5 days later and death from liver failure.(8) Renal damage, sometimes leading to renal failure, can occur up to 14 days later even without evidence of liver damage.(9) The cytotoxicity of acetaminophen is now known to be mediated by a reactive metabolite (oxidizing agent) normally detoxified by glutathione. When cellular glutathione levels become depleted to less than 25% of normal, cell death can result. When given within 12 hours of ingestion, NAC prevents acetaminophen-induced cellular damage. By supplying the cells with a means of producing glutathione, NAC helps maintain cellular glutathione levels, preventing cell death. NAC is much less effective when given much later than 12-16 hours after acetaminophen overdose, as the glutathione formed from NAC can prevent oxidant-derived cellular damage, but cannot reverse it. In the years following the discovery of its usefulness in acetaminophen poisoning, it was proven that NAC worked because it was an antioxidant and was converted to glutathione, an even more potent antioxidant.(10) The ensuing research has shown NAC to be much more than the mucolytic it was once regarded as. For example, NAC is itself an antioxidant. It has the capacity to scavenge hydrogen peroxide, hypochlorous acid, and the hydroxyl radical.(11) Most of its antioxidant potential, however, is due to its rapid metabolism to glutathione. In this form NAC has demonstrated the ability to decrease membrane damage from superoxide-generating systems,(12) as well as prevent damage to human bronchial fibroblasts from tobacco smoke condensates.(13) Recent years have shown NAC receiving growing interest among both scientists and physicians, due to the enormous role that oxidation and free-radical mediated damage plays in so many conditions and diseases. In fact, NAC has been a featured topic of several international symposia on the potential of antioxidants as therapeutic agents,(14) as well as being a supplement in a large cancer chemoprevention trial currently taking place in Europe.(15)

Part 2

In part 1 of our examination of N-Acetyl Cysteine (NAC), we reviewed the metabolism and antioxidant properties of NAC. We will continue our review of NAC with an overview of the clinical and experimental evidence of NAC's potential in lung disorders, and its role in immune function.

NAC and Lung Disorders

The use of NAC as a treatment for bronchitis was its first clinical use over 30 years ago. NAC's ability to liquefy the mucus (mucolytic) that contributes to this condition has been utilized in Europe and the rest of the world for decades. Oral NAC has been shown to decrease the exacerbation rate in people with chronic bronchitis.(16) NAC has also been used with success in people with Chronic Obstructive Pulmonary Disease, Adult Respiratory Distress Syndrome, and emphysema.(17) Research into lung disorders other than bronchitis, as well as NAC's emergence from mucolytic to antioxidant, has caused NAC to be viewed as a compound with potential usefulness in many respiratory disorders and diseases.

NAC and Immune Function

One of the most exciting areas of NAC research is in the area of immunology. It is generally accepted that immune responses are mediated by hormonelike peptides, such as cytokines and lymphokines. However, other low-molecular weight metabolites have the ability to regulate immune function. One of the best researched of this class of immunoregulatory substances is the amino acid cysteine. Because the activation and proliferation of T cells normally requires oxidizing substances such as superoxide and hydrogen peroxide, lymphocytes contain a limited amount of reducing substances such as cysteine.(18) Interestingly, unlike most other cells, lymphocytes can utilize cysteine or NAC for glutathione production, but not cystine.(19) Thus, lymphocytes are very sensitive to the levels of extracellular cysteine. Cysteine, however, is found in the lowest concentration of all protein-forming amino acids in the blood. It is during the interchange

between lymphocytes and macrophages that the macrophages consume cystine from the blood plasma, and release cysteine to stimulate T-cell respones.(20) In the course of the activation of T-cells, macrophages come into contact with T-cells and transfer among other immunochemicals, cysteine. This transfer of cysteine ensures adequate glutathione production for optimal T-cell proliferation. Indeed, NAC has been found to significantly enhance human T-cell function, especially in older individuals.(21)

No illness has contributed more to our understanding of the potential roles of cysteine and its precursor NAC in immune function than HIV infection and AIDS. Cysteine and glutathione levels have been found to be significantly depressed in people with HIV infection and AIDS.(22) In fact, this depression of cysteine and glutathione levels has been observed in patients at all stages of the disease, including those presenting no symptoms and appearing healthy. Many researchers feel that this glutathione deficiency

plays a major role in the pathogenesis of HIV and the eventual development of AIDS. NAC is currently undergoing clinical trials around the world as an augmenter of immune function in people with AIDS. It has shown the ability to not only restore cysteine and glutathione levels, but also to inhibit the replication of HIV.(23) It has even been suggested that NAC's ability to inhibit latent HIV expression may slow the development of HIV infection to active AIDS.(24) Unfortunately, as many researchers have lamented, NAC as an approved therapeutic for AIDS continues to wallow in small-scale clinical trials. It is unconscionable that a compound with very impressive laboratory results against HIV, along with a 30 year track record of safety in Europe, could be mired in clinical trials that will not only take years to complete, but will examine primarily NAC's usefulness in full-blown AIDS. This totally ignores NAC's greatest potential, its ability to possibly prevent the progression to AIDS from asymptomatic HIV-infection.

Using NAC+

With its well-documented superiority as a stable source of cysteine and precursor of glutathione, NAC appears to be a very useful dietary source of cysteine. The obvious question then is how much supplemental NAC is adequate or desirable. In its long use as a therapy for respiratory diseases and conditions, NAC has been utilised at dosages from 200 milligrams to 1800+ milligrams daily. NAC has been given both in divided doses and as one daily dose, usually with equal effectiveness. Higher doses have been utilised in more severe disease states, while lower doses have been used in less severe illness. For general use as an antioxidant, most of us would want to consume from 250 milligrams to 1200 milligrams daily. People exposed to large amounts of oxidants and glutathione depleters, such as smokers, would probably want to take an amount of NAC at the upper level of this range. For other uses, such as in HIV infection and severe lung conditions, larger doses may be necessary for optimum results. However, persons with such conditions wishing to take large amounts of NAC should do so under a physician's care. This is not due to any NAC-associated toxicity, as none has been reported, but rather because you should not attempt to self-medicate serious conditions such as HIV infection or lung diseases. One last consideration with NAC is the consumption of other antioxidants, such as vitamin C, vitamin E, and selenium. While almost all studies to date have examined NAC supplements when taken alone, other antioxidants and vitamins that play a role in the metabolism and regeneration of glutathione should enhance NAC's properties.

Part 3

NAC and Carcinogenesis

One of the most exciting areas of research into the potential benefits of N-Acetyl Cysteine (NAC) is that of cancer chemoprevention. Numerous studies have documented antimutagenic effects of NAC against a wide variety of mutagenic chemicals and mixtures.(25) In addition, NAC displays anticarcinogenic effects in various organs of rodents, including the mammary glands, skin, trachea, lung, bladder, and colon.(26) Because of this experimental evidence, NAC is considered one of the most promising

chemopreventative agents. In fact, it is currently under investigation in clinical intervention trials in both the U.S. and Europe for the prevention of second primary tumours in patients previously treated for cancer of the oral cavity, larynx, and lung.(27)

The mechanisms of action for NAC's antimutagenic and anticarcinogenic properties has been shown to be multifaceted. To begin with, it detoxifies direct-acting mutagens such as superoxide, hydrogen peroxide, and singlet oxygen due to its antioxidant activity.(28) NAC also inhibits the mutagenicity of procarcinogens such as cigarette smoke condensate, benzo(a)pyrene, and aflatoxin by binding with their metabolites.(29) Inside cells, NAC is rapidly converted to cysteine and then glutathione. As a result, NAC enhances the detoxification of carcinogens inside cells. The glutathione formed from NAC effectively blocks electrophilic compounds and metabolites, as well as efficiently scavenging reactive oxygen species. Glutathione also protects against the down regulation of nuclear enzymes that is produced by carcinogens, decreases carcinogen-induced DNA damage, and prevents the ultimate formation of carcinogen-DNA adducts.(30) All of these mechanisms contribute to NAC's anticarcinogenic effects by inhibiting the initiation of the carcinogenic process, as well as the later promotion stage of carcinogenesis. The ability of NAC to prevent carcinogen-DNA adducts offers hope for more than preventing cancer. For instance, multiple DNA adducts were found not only in the lung, but also in the heart and aorta in cigarette smoke exposed rats. Administration of NAC to these animals inhibited the formation of these carcinogen-DNA adducts in all organs.(31) These authors raised the hypothesis that while, for instance, NAC inhibits dominant lethal mutations by lowering DNA adduct formation in the testes, DNA adduct formation in other organs could explain numerous consequences of carcinogen exposure. They hypothesised that DNA adducts in the lung, heart, and aorta may be pathogenically related with lung cancer, cardiomyopathies, and arteriosclerosis. This hypothesis was supported by evidence that DNA adducts can be detected in human aorta smooth muscle cells from arteriosclerotic patients. In its role as an inhibitor of DNA adduct formation in various organs and tissues, NAC may be a potent protector of not only cancer, but a wide variety of degenerative diseases.

References:

1) A.L. Sheffner, Ann NY Acad Sci 1963; 106: 298-310.
2) I.A. Cosgreave, A. Eklund, K. Larsson, et al, Eur J Respir Dis 1987; 70: 73-77. Editorial, Eur J Respir Dis 1987; 70: 71-72.
3) T.J. Slaga, in: Carcinogenesis Vol. 5: Modifiers of Chemical Carcinogenesis (Ed. T.J. Slaga). p. 111. Raven Press, New York (1980).
4) M. Holdiness, Clin Pharmacokinetics 1991; 20: 123-134.
5) M.M.E. Bridgeman, M. Marsden, W. MacNee, et al, Thorax 1991; 46: 39-42.
6) J.M. Estrela, G.T. Saez, L. Sucha, et al, Biochem Pharm 1983; 32: 3485-3487. L. DeCaro, A. Ghizzi, R. Costa, et al, Arzneimettel-Forschung 1989; 39: 382-386.
7) E. Piperno, D.A. Berssenbruegge, Lancet 1976; 2: 738.
8) L.F. Prescott, Drugs 1983; 25: 290-314.
9) L.F. Prescott, A.T. Proudfoot, R.J. Cregeen, Br Med Journal 1982: 284: 421-422.
10) R.J. Flanagan, T.J. Meredith, Am J Med 1991; 91 (Suppl. 3C): 131s-137s.
11) O.I. Aruoma, B. Halliwell, B.M. Hoey, et al, Free Rad Biol Med 1989; 6: 593-597.
12) S. DeFlora, A. Izzotti, F. D'Agostini, et al, Am J Med 1991; 91 (Suppl. 3C): 122s-130s.
13) P. Moldeus, I.A. Cotgreave, M. Berggren, Respiration 1986; 50 (Suppl. 1): 31-42.
14) R.G. Crystal, A. Bast, et al, Am J Med 1991; 91 (Suppl. 3C).
15) G.J. Kelloff, C.W. Boone, W.F. Malone, J Cell Biochem 1992; 161 (Suppl.): 1-72.

Part 2
16) Multicenter Study Group, Eur J Resp Dis 1980; 61 (Suppl. 111): 93-108. G. Boman, U. Backer, S. Larsson, et al, Eur J Resp Dis 1983; 64: 405-415. British Thoracic Research Commitee, Thorax 1985; 40: 832-835.
17) P. Suter, G. Domenighetti, M.D. Schaller, et al, Chest 1994; 105: 190-194. G.R. Bernard, Am J Med 1991; 91 (Suppl. 3C): 54s-59s. W. MacNee, M.M.E. Bridgeman, M. Marsden, Am J Med 1991; 91 (Suppl. 3C): 60s-69s.
18) W. Droge, H.P. Eck, H. Gmunder, et al, Am J Med 1991; 91 (Suppl. 3C): 140s-144s.
19) H. Gmunder, H.P. Eck, W. Droge, Eur J Biochem 1991; 201: 113-117. See also reference18.
20) H. Gmunder, H.P. Eck, B. Benninghoff, et al, Cell Immunol 1990; 129:32-46.
21) E. Eylar, C. Rivera-Quinones, C. Molina, et al, Int Immunol 1993; 5:97-101.
22) F.J.T. Staal, M. Roederer, D.M. Israelski, et al, AIDS Res Human Retroviruses 1992; 2: 311. R. Buhl, K.J. Holroyd, A. Mastrangeli, et al, Lancet 1989; 2: 1294.
23) M. Roederer, S. Ela, F.J.T. Staal, et al, AIDS Res Human Retroviruses 1992; 8:209-217.
24) M. Roederer, P.A. Raju, F.J.T. Staal, et al, AIDS Res Human Retroviruses 1991; 7: 563-570.

Part 3
25) S. DeFlora, A. Izzotti, F. D'Agostini, et al, in: Cancer Chemoprevention (Eds., L. Wattenberg, et al), pp. 183-194. CRC Press, Boca Raton, FL (1992). N.DeVries, S.DeFlora, J Cell Biochem 1993; Suppl. 17F: 270-277.
26) A. Izzotti, F. D'Agostini, M. Bagnasco, et al, Cancer Res 1994; 54 (Suppl.):1994s-1998s.
27) See reference 15.
28) S. DeFlora, A. Izzotti, F. D'Agostini, et al, Am J Med 1991; 91 (Suppl.3C): 122-130.
29) S. DeFlora, C. Bennicelli, A. Camoirano, et al, Carcinogenesis 1985; 6:1735-1745.
30) A. Izzotti, R. Balansky, N. Coscia, et al, Carcinogenesis 1992; 13:2187-2190.
31) See reference 26.

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