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Chester Myers' Nutrition Series

HIV and Nutrition: Rationale for NAC

Introduction
In 1988 we had, to my knowledge, the first recommendations for supplementation with N-acetyl cysteine - commonly known as NAC. This recommendation was from a German research group which was one of the first to document deficiencies of cysteine, glutathione and related compounds in HIV disease. (Dröge et al, 1988; Dröge et al, 1993)

Since 1988 we have had many more reports about deficiencies of glutathione and related compounds. These compounds fall under the broad category of thiols which means they contain sulphur. (Anderson et al, 1993; de Quay et al, 1992; Castagna et al, 1995; Galera et al, 1996; Hack et al, 1997; Helbling et al, 1996; Holroyd et al, 1993; Jarstrand and Åkerlund, 1994)

In HIV disease, a decrease in the levels of the body's thiols correlates with elevated levels of oxidative compounds, i.e., compounds that tend to cause damage, and whose activity should be mainly for the destruction of infections, not our bodies. Many of these oxidative compounds are produced by the immune system. The body normally prevents them from existing for long periods of time, and restricts them to the sites of infection. The immune system also increases its production of antioxidants to protect the body from these oxidative compounds it uses to fight infection. At the same time, at least some of the immune cells increase their uptake of compounds such as vitamins C and E, even though they already contain higher levels than do other cells of the body. (Bendich, 1990; Boxer, 1990; Buhl, 1994; Lopez et al, 1996; Reed, 1993)

In the monkey model, a German research group has observed that cysteine deficiency starts within a few days of infection . If this is so in humans, then it is the earliest observed event in the course of HIV disease. Otherwise, deterioration of the gut lining qualifies for this distinction. (Batman et al, 1989; Eck et al, 1991; La Brooy, 1993; Ott et al, 1993; Ullrich et al, 1989)

At a major conference on HIV and oxidative stress in 1993 one research group practically defined AIDS as a consequence of an HIV induced cysteine deficiency: "Several lines of evidence suggest that AIDS may be the consequence of a virus-induced cysteine deficiency." (Dröge et al, 1993)

Thiols often function as antioxidants in the body, although as with all antioxidants, we must keep in mind that, depending on what other compounds are present, they may also act as oxidants. Lipoic acid is another thiol some may be familiar with. It is of special importance for the liver, and has been studied for its benefits in HIV disease. There are also other functions for thiols in the body, besides being oxidants or antioxidants (reductants). (Fuchs et al, 1993; Han et al, 1995; Merin et al, 1996; Sen et al, 1997; Suzuki et al, 1995)

About Cysteine
Cysteine, which the body produces from NAC, is one of two sulphur-containing amino acids which are building blocks for proteins and other compounds of the body. The other amino acid that contains sulfur is called methionine. Most proteins, including the muscle tissues and most enzymes, require these as building blocks.

Some of the body's compounds that depend on cysteine are:

Metallothionein - a protein that is approximately 30% cysteine. (It sometimes is also referred to as one of the body's superoxide dismutases (SOD).) Metallothionein regulates body levels of zinc and copper. It is also related to sulphur-containing compounds that help in zinc absorption from the small intestine. So, with either low body thiols or if they are excessively oxidized in HIV disease, it is likely that both zinc absorption from the gut and its balance with copper in the body are likely to be defective. This must not be healthy, since zinc is important for many proteins including some of the digestive and immune systems. (Benard and Balasubramanian, 1993, 1995; RJ Cousins, 1988; O'Dell, 1992)

Trypsin, an enzyme from the pancreas. It releases several other enzymes important for digestion. The body places a high priority on this, and when cysteine is deficient in the diet, the body cannibalizes muscle protein as an alternate source of cysteine for trypsin. This leads to wasting , and is perhaps the most direct of the various routes whereby a cysteine deficiency may result in loss of lean body mass. (Gross et al, 1996; L Thompson, personal communication)

Glutathione, a tripeptide made from three amino acids, glycine, glutamate (which can be derived from glutamine), and cysteine, functions largely as an antioxidant in the body. It is regarded as one of the most important antioxidants. Like lipoic acid, it is in every cell of the body, and is important especially for protecting the body from the oxidants that the immune system produces to destroy infections (during the "oxidative" or "respiratory burst"). Apparently because of this, glutathione is produced by cells of the immune system, especially the macrophages whose production of glutathione elevates during a fight to destroy infection.

Levels of glutathione are particularly high also in the liver and lining of the lungs. Along with vitamin C, it appears to be the only major antioxidant defense of the eyeball - low glutathione is associated with increasing tendency for cataract formation. Not surprisingly, glutathione is the thiol that has received most attention in HIV disease.

About Glutathione
One aspect about glutathione that is typical of the inter-relatedness of so many nutritional issues, is that a magnesium deficiency may manifest itself in low glutathione in certain cells - at least in animal (rat) model study. Magnesium deficiencies are one of the most common in HIV disease, yet this issue is often overlooked. While I will make no secret of my support for NAC supplementation, I also would advise that we must make sure we do not simply mask some other deficiency - this oxidative stress from magnesium deficiency might be masked by vitamin E and other antioxidants in the absence of a more general supplementation program that includes magnesium. For those with HIV/AIDS, it is advisable to have serum magnesium monitored every six months. (Mak et al, 1994)

Several functions of glutathione in the body require certain enzymes of which glutathione peroxidase may already be familiar, largely because of (1) its dependence on the mineral selenium for its activity, and (2) its ability to slow down activation of HIV-1 that results from oxidative stress. (Gilliland, 1993; Sappey et al, 1994)

Although glutathione is well-recognized as an important compound for the body's fight against disease, including HIV disease, three functions of glutathione that are largely overlooked are relevant (1) to immunity, (2) to Kaposi's Sarcoma development, and (3) metabolic abnormalities that have been observed to occur in HIV infection.

  • The first of these is that glutathione encourages production of Interleukin-2. Interleukin-2 is an important cytokine produced by the immune system, and which helps regulate immunity. Generally, in HIV disease, it is regarded as one of the cytokines that needs to be bolstered, and direct administration of it is being examined as an immunity rejuvenant. There is also evidence that glutathione has a controlling effect on one type of apoptosis that is induced by one of the prostaglandins. (Kim et al, 1996; Wu et al, 1994; Yamauchi and Bloom, 1993)
  • (2) Secondly, it has been observed in the test tube that thiols inhibit one of the mechanisms involved in KS development. (Offermann et al, 1996)
  • (3) Glutathione helps modulate thyroid activity via its relationship with an enzyme, thioredoxin, which helps recycle iodine in the body. It is possible that dysfunction of this system, as a result of low glutathione, is the source of some of the metabolic abnormalities that have been documented in HIV, via endocrine dysfunction. (Das et al, 1988; Hellerstein, 1992; Goswami & Rosenberg, 1987)
About the eicosanoids
Related to the potential role for cysteine deficiency in KS development are certain regulatory compounds the body makes from our dietary fat. These compounds are the eicosanoids - thromboxanes, leukotrienes and prostaglandins. They tend to work in pairs, one turning on, another turning off functions as varied as stomach emptying, blood flow into capillaries and helping sperm to impregnate the egg. It seems that the prostaglandins have also facilitated infection from HIV-containing sperm to the walls of whatever human membrane is exposed to that sperm. (e.g., see Hunt and Groff, 1990; Konturek et al, 1997; Serrano et al, 1997)

Some of the eicosanoids cause inflammation, and their production is suppressed by anti-inflammatory materials such as fish oil, aspirin, flavonoids and other compounds. Many of them - such as certain prostaglandins already mentioned - tend to be immunosuppressive and it is partly because of this that certain dietary fats such as those from soy, corn, sunflower and safflower are associated with immune suppression. (Hardardottir, 1993; Kinsella et al, 1990)

Some of the leukotrienes are directly involved in blood capillary function, and it may be that a dysfunction here is partly involved in KS. It is interesting that formation of these leukotrienes involves glutathione, and indeed some leukotrienes are themselves thiols, i.e., in their final form, they contain sulphur. As an aside, it seems one of the mechanisms of immune suppression by PGE(2) is by a resulting decrease in glutathione generation. (Mayatepek et al, 1993;Yu et al, 1993; also see Suzuki et al, 1997 re reaction between glutathione and certain prostaglandins )

Why Deficiencies?
At the best of times, the sulphur-containing amino acids in our food's proteins tend to be limiting, and many foods contain lower levels than are regarded as adequate. Furthermore, during food processing, especially during heat treatments, the thiols are particularly sensitive to destruction (oxidation).

Some will be familiar with a new whey protein isolate that is being studied in HIV disease in Dr. LaLonde's group at McGill University. In Canada this is known by the name HMS 90, in the USA it is called ImmuneCal™. Special precautions have been taken to preserve the thiols of this whey protein isolate in an unoxidized form. When used as a protein supplement in a drink, to prevent oxidation, even by simple air incorporation, it is NOT recommended to use a blender.

Both cysteine and methionine become oxidized, first to reversibly oxidized forms, then, with harsher conditions, to irreversibly oxidized forms that are metabolically unavailable other than for synthesis of taurine. (Viswanatha, personal communication; Brot & Weissbach, 1982)

Cysteine vs NAC
Why not supplement directly with cysteine, the amino acid that is missing? This is possible, but there are concerns over toxicity, especially to the central nervous system. It seems that oxidation of cysteine in the stomach generates toxic material that is especially associated with neurotoxicities. NAC, on the other hand, is non-toxic at even high levels. It has been used for bronchitis at gram quantities. Its use has also been considered in various other states of disease. It is generally considered non-toxic. (PukaSundvall et al, 1995)

Reported benefits of NAC
I suppose the most straightforward benefit of NAC is that hospitals keep a solution of NAC, called Mucomyst, for Tylenol poisoning which is via depletion of the body's glutathione. In HIV disease, while long term NAC use has been found to replenish glutathione, in the short term, this has been difficult to document, although cysteine levels per se are observed to increase.

Acetaminophen-containing medications such as Tylenol would seem dangerous for those with suppressed immune systems. Acetaminophen is converted in the liver to a highly oxidative benzoquinone which destroys glutathione. When glutathione levels are low in the body, it takes less acetaminophen to cause severe toxicity than is necessary in healthy people. Furthermore, it has been observed that people with HIV infection produce elevated levels of oxidative metabolites from acetaminophen. (Esteban et al, 1997; Kaplowitz et al, 1989; Zhou et al, 1997)

In the absence of HIV, there are a number of studies, mainly relating to lung disease, that show glutathione levels are increased with NAC. (Bridgeman et al, 1994; Meyer et al, 1995)

One research group has shown that supplementation with NAC, at 400 mg per day for 3 days per week, helps thwart weight loss, especially of lean body mass, during exercise in people who do not have HIV, and have speculated that NAC is important for those with HIV for this reason alone. (Kinscherf et al, 1996)

Another important result is the halting of apoptosis which is a source of death to cells of the immune system in HIV. Luc Montagnier, one of the co-founders of HIV, has stated this in interview with Dr. Passwater of the Solgar company. This effect is observed only after 6 months of supplementation at from 600 to 1800 mg per day (a 3 year study). This effect is apparently due to the direct antioxidant activity of NAC and an ability to restore glutathione levels, although elevation of the enzyme glutathione peroxidase has been shown also to occur. (Olivier et al, 1993; Sandstrom et al, 1994)

NAC is observed in test tube studies to suppress a compound called NF kappa B. This compound is increased when glutathione is low and it encourages viral growth. (Breithaupt et al, 1996; Mihm et al, 1995)

Results were reported in 1994 from a Mexican study of NAC in combination with antiretroviral therapy. Three groups of 100 HIV+ people were given respectively, AZT, AZT + ddC, and AZT + ddC + NAC. At the end of one year, there were considerable improvements in the NAC wing of the study, relative to the other two wings. These improvements included higher CD4 counts and fewer AIDS-related illnesses. (Feregrino-Goyos et al, 1994)

Results from a Swedish double-blind placebo-controlled intervention study found that 800 mg of NAC slowed the decline of CD4 counts, and decreased tumour necrosis factor alpha, which is otherwise often too high in HIV disease. (Åkerlund et al, 1996)

A research group from Stanford University noted several years ago that high levels of glutathione are associated with survival, and that NAC supplementation from 3200 to 8000 mg daily elevates glutathione. More recently we have had yet more up-to-date results from this group, noting benefits after as little as 8 weeks of NAC supplementation. These results were presented at another conference on oxidative stress, and then were published in the scientific literature. (Herzenberg et al, 1997)

Thus, there is evidence that NAC helps thwart wasting, normalizes apoptosis, normalizes glutathione levels, and slows the decline of CD4+ cells in HIV disease. At a personal level, it became apparent to me that as early as 1992, my friends who were taking NAC were doing much better living with HIV.

Benefits have been reported from supplementation with 400 mg to 1.5 grams a day, although levels even to 8 grams have been examined. Above, 8 grams however, there can be problems with stomach distress. One doctor suggested at the 1994 HIV/Nutrition meeting in Philadelphia a daily intake of about 3 grams. Dr. Jon Kaiser, on the other hand recommends 1.5 grams in his nutritional recommendations. In animal studies, administered levels of NAC is often given on a per weight basis, but in most cases the level is much higher than any of the levels recommended in HIV disease. Over the counter varieties have been analyzed both in New York and in Toronto - all contained what was claimed.

Not only do I believe it makes sense to take NAC, but I think any study in this area should look more at trying to determine the best level, rather than trying to do a study of some vs none.

Conclusion
I have given here what is a general concensus by many researchers of the area. There have been some test tube studies that did not indicate benefits of NAC, and even indicated potential harm. However, these results have not been upheld in studies in either animals nor humans. In one human study, however, a 2 week NAC treatment was observed not to increase glutathione levels in certain parts of the body. Several studies have indicated also that the body still exercises its normal control over preventing undue excessive antioxidant behaviour by cysteine, and also prevention of harmful oxidation. (Chen et al, 1996; Simon et al, 1994; Witschi et al, 1995)

Another problem in these studies is the ease of destruction of the thiols after blood collection. This and frank overlooking of the chemistry of these materials have resulted in publication of some conflicting data. Associated with this is the problem of total thiol levels vs the balance between the oxidized and reduced forms. There is also variation in thiol status depending on stage of HIV disease. Again, this has caused some confusion. (Aukrust et al, 1995; Barditch-Crovo et al, 1995; Pacht et al, 1977; Palamara et al, 1996; Pirmohamed et al, 1996)

There have been studies looking at potential direct antiviral activity. It seems that NAC does NOT act in the body directly as an antiviral, although in the Mexican study it apparently helped other antivirals to do a better job. This may be because in the long term glutathione is raised, and this demonstrates antiviral behaviour at least in an indirect way. A direct mechanism has also been proposed. (Kameoka et al, 1996; Palamara et al, 1996)

Of course, we can still fine tune. For example, one area that is being examined in a Florida arm of one of the studies by Dr Shabert from Boston is the role of glutamine and NAC. After cysteine, glutamine is the next limiting amino acid in the synthesis of glutathione, and a role has been suggested for this by several studies. (Denno et al, 1996; Kinscherg et al, 1996)

My personal interest here would be to encourage more epidemiology type studes. I think
  • lower incidence of CMV retinitis,
  • less development of Kaposi's Sarcoma,
  • less sensitivity to Septra,
  • less lactose intolerance,
  • less hypertriglyceridemia,
  • fewer abnormalities in homocysteine levels, and
  • less wasting,
would all be worthwhile examining as having possible association with use of NAC. (Castagna et al, 1995; Denno et al, 1996; Kinscherf et al, 1996; Lehmann et al, 1996; Müller et al, 1996; Robinson et al, 1992; Wiklund et al, 1996)

Finally, while this has been to do largely as an argument for supplementation, we must not forget that there are also data indicating increases in body thiols from certain foods, and not only the whey proteins, but also foods such as garlic and the cruciferous family (Brussels sprouts, broccoli, cabbage, cauliflower). (Baruchel et al, 1994; Bogaards et al, 1994; Bounous et al, 1993; Chen et al, 1995)

Representative References re NAC
B Åkerlund, C Jarstrand, B Lindeke, A Sönnerborg, A-C Åkerlund, O Rasool, "Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial", Eur J Clin Pharmacol 50:1996:457-461.

MT Anderson, FJT Staal, M Roederer, C Gitler, LA Herzenberg, LA Herzenberg, "Decreased Glutathione in those HIV infected may account for decreased proliferative responses and increased inflammatory stress", abstract, Conference on Oxidative Stress in HIV/AIDS - A Potential for Therapies, NIH, Maryland, Nov 8-10, 1993).

P Aukrust, AM Svardal, F Müller, B Lunden, RK Berge, PM Ueland, SS Frøland, "Increased levels of oxidized glutathione in CD4(+) lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency virus type I infection", Blood 86:1995:258-267.

P Barditch-Crovo, V Svobodova, P Lietman, "Apparent Deficiency of Glutathione in the PBMC's (sic) of People with AIDS Depends on Method of Expression", letter to the editor, JAIDSHR 8:1995:313-314.

S Baruchel, G Bounous, P Gold, "Place for an antioxidant therapy in human immunodeficiency virus (HIV) infection", in Oxidative Stress, Cell Activation and Viral Infection, ed. C Pasquier et al, Birkhäuser Verlag, Basel, 1994.

PA Batman, ARO Miller, SM Forster, JRW Harris, AJ Pinching, GE Griffin, "Jejunal Enteropathy Associated with Human Immunodeficiency Virus Infection: Quantitative Histoloty", J Clin Pathol 42:1989:275-282.

O Benard, KA Balasubramanian, "Effect of Oxidant Exposure on Thiol Status in the Intestinal Mucosa", Biochem Pharmacol 45:1993:2011-2015.

O Benard, KA Balasubramanian, "Effect of oxidized glutathione on intestinal mitochondria and brush border membrane", Internat J Biochem Cell Biol 27:1995:589-595.

A Bendich, "Antioxidant Nutrients and Immune Functions - Introduction", pp 1-12 Antioxidant Nutrients and Immune Function, ed A Bendich, M Phillips, RP Tengerdy, Plenum Press (Advances in Experimental Medicine and Biology, v 262, 1990).

JJP Bogaards, H Verhagen, MI Willems, G Vanpoppel, PJ Vanbladeren, "Consumption of Brussels sprouts results in elevated alpha-class glutathione S-transferase levels in human blood plasma", Carcinogenesis 15:1994:1073-1075.

G Bounous, S Baruchel, J Falutz, P Gold, "Whey Proteins as a Food Supplement in HIV-Seropositive Individuals", Clin Invest Med 16:1993:204-209.

LA Boxer, "The Role of Antioxidants in Modulating Neutrophil Functional Responses", pp 19-33 Antioxidant Nutrients and Immune Function, ed. A Bendich, M Phillips, RP Tengerdy, Plenum Press (Advances in Experimental Medicine and Biology, v 262, 1990).

TB Breithaupt, A Vazquez, I Baez, EH Eylar, "The suppression of T cell function and NF kappa B expression by serine protease inhibitors is blocked by N-acetylcysteine", Cell Immunol 173:1996:124-130.

MME Bridgeman, M Marsden, C Selby, D Morrison, W Macnee, "Effect of N-acetyl cysteine on the concentration of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue", Thorax 49:1994:670-675.

N Brot, H Weissbach, "The biochemistry of methionine sulfoxide residues in proteins", TIBS April:1982:137-139.

R Buhl, "Imbalance between oxidants and antioxidants in the lungs of HIV-seropositive individuals", Chemico- Biological Interactions 91:1994:147-158.

A Castagna, C Le Grazie, A Accordini, P Guilidori, G Cavalli, T Bottigliere, A Lazarrin, "Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: Effect of parenteral treatment with SAMe", Neurology 45:1995:1678-1683.

MF Chen, LT Chen, HW Boyce, "Cruciferous vegetables and glutathione: Their effects on colon mucosal glutathione level and colon tumor development in rats induced by DMH", Nutrition and Cancer - an International Journal 23:1995:77-83.

P Chen, G Bauer, J Mitchell, R Factor, R Markham, DH Schwartz, "N-acetyl-cysteine and L-2-oxathiazolidine-4-carboxylic acid enhance contact-dependent growth of HIV in resting peripheral blood mononuclear cells (PBMC) in vitro and increase recovery of HIV from human-PBMC mice", AIDS 11:1997:33-41.

RJ Cousins, "Molecular Biology and Micronutrient-Disease Relationships - Zinc as a Prototype", Chap 1 in Nutrition and the Origins of Disease, ed CH Halsted, RB Rucker, Academic Press, 1988.

AK Das, BCW Hummel, FK Gleason, A Holmgren, PG Walfish, "Bacterial and mammalian thioredoxin systems activate iodothyronine 5' -deiodination", Biochem Cell Biol 66:1988:460-464.

R Denno, JD Rounds, R Faris, LB Holejko, DW Wilmore, "Glutamine-enriched total parenteral nutrition enhances plasma glutathione in the resting state", J Surg Res 61:1996:35-38.

B de Quay, R Malinverni, BH Lauterberg, "Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine", AIDS 6:1992:815-819.

W Dröge, H-P Eck, H Naher, U Pekar, V Daniel, Biol Chem Hoppe-Seyler 369:1988:143-148 (also see Dröge et al, Immunol. Today 13:1992:211-214). These are 'second hand' references taken from Dröge et al, abstract, Conference on Oxidative Stress in HIV/AIDS - A Potential for Therapies, NIH, Maryland, Nov 8-10, 1993).

W Dröge, S Mihm, J Ennen, U Pessara, R Kurth, "Demonstration of cysteine and glutathione deficiency in HIV-infected patients. Inhibition of HIV-Replication and Nf- B activity by cysteine and cysteine derivatives", abstract, Conference on Oxidative Stress in HIV/AIDS - A Potential for Therapies, NIH, Maryland, Nov 8-10, 1993).

H-P Eck, C Stahl-Hennig, G Hunsmann, W Dröge, "Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques", Lancet 338:1991:346-347.

A Esteban, M PerezMateo, M Gonzalex, M Portilla, A Mora, "Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus (HIV)", Methods and Findings Exp Clin Pharmacology 19:1997:129-132.

M Feregrino-Goyos, "AZT Monotherapy compared to AZT+DDC combined antiviric therapy and AZT+DDC+NAC (100 patients each group)", abstract PB0260, Vancouver International AIDS Conference.

J Fuchs, H Schofer, R Milbradt, HJ Freisleben, R Buhl, W Siems, T Grune, "Studies of Lipoate Effects on Blood Redox State in Human Immunodeficiency Virus Infected Patients", Arzneimittel - Forschung/Drug Res 43:1993:1359-1362.

RML Galera, JCJ Gimenez, RBM Ronsano, RMS Cardona, MAA Via, CA Roca, JMT Puigbert, "Glutathione and cysteine in HIV-infected hemophiliacs", Clin Chim Acta 254:1996:63-72.

GL Gilliland, "Glutathione proteins", Current Opinion in Structural Biology 3:1993:875-884.

A Goswami, IN Rosenberg, "Thioredoxin stimulates enzymatic outer ring monodeiodination of revers triiodothyronine", Endocrinology (Baltimore) 121:1987:1937-1945.

A Gross, V Hack, C StahlHennig, W Dröge, "Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus monkeys", AIDS Res Human Retroviruses 12:1996:1639-1641.

V Hack, D Schmid, R Breitkreutz, C StahlHenning, P Drings, R Kinscherf, F Taut, E Holm, W Dröge, "Cystine levels, cysteine flux, and protein catabolism in cancer cachexia, HIV/SIV infection, and senescence", FASEB J 11:1997:84-92.

D Han, HJ Tritschler, L Packer, " -Lipoic Acid Increases Intracellular Glutathione in a Human T-lymphocyte Jurkat Cell Line", Biochem Biophys Res Commun 207:1995:258-264.

I Hardardottir, J Whelan, ME Surette, KS Broughton, GP Lu, EC Larsen, JE Kinsella, "The Effects of Dietary n-3 Polyunsaturated Fatty Acids and Cyclic AMP-Elevating Agents on Tumor Necrosis Factor Production by Murine-Resident and Thioglycollate-Elicited Peritoneal Macrophages", J. Nutr. Biochem. 4(1993)534-542.

B Helbling, V VonOverbeck, BH Lauterberg, "Decreased release of glutathione into the sytemic circulation of patients with HIV infection", Eur J Clin Invest 26:1996:38-44.

Hellerstein, M. K., "Pathophysiology of Lean Body Wasting and Nutrient Unresponsiveness in HIV/AIDS: Therapeutic Implications", Proc. of the 1992 International Symposium on Nutrition and HIV/AIDS, Nutrition & HIV/AIDS, 1:1992:17-25.

LA Herzenberg, SC De Rosa, JG Dubs, M Roederer, MT Anderson, SW Ela, SC Deresinski, LA Herzenberg, "Glutathione deficiency is associated with impaired survival in HIV disease", Proc Natl Acad Sci USA 94:1997:1967-1972.

KJ Holroyd, R Buhl, Z Borok, JH Roum, AD Bokser, GJ Grimes, D Czerski, AM Cantin, RG Crystal, "Correction of Glutathione Deficiency in the Lower Respiratory Tract of HIV Seropositive Individuals by Glutathione Aerosol Treatment", Thorax 48:1993:985-989.

SM Hunt, JL Groff, Advanced Nutrition and Human Metabolism, West Publishing Co. 1990.

C Jarstrand, B Åkerlund, "Oxygen radical release by neutrophils of HIV-infected patients", Chemical-Biological Interactions 91:1994:141-146.

M Kameoka, Y Okada, M Tobiume, T Kimura, K Ikuta, "Intracellular glutathione as a possible direct blocker of HIV type I reverse transcription", AIDSRHR 12:1996:1635-1638.

N Kaplowitz, J Fernandez-Checa, M Ookhtens, "Glutathione, Alcohol, and Hepatotoxicity", in Nutrition and the Origins of Disease, ed. CH Halsted, RB Rucker, Academic Press, 1989.

HS Kim, JH Lee, IK Kim, "Intracellular glutathione level modulates the induction of apoptosis by Delta(12)-prostaglandin J(2)", Prostaglandins 51:1996:413-425.

R Kinscherf, V Hack, T Fischbach, B Friedmann, C Weiss, L Edler, P Bärtsch, W Dröge, "Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N-acetyl-cysteine", J Mol Med 74:1996:393-400.

JE Kinsella, B Lokesh, S Broughton, J Whelan, "Dietary Polyunsaturated Fatty Acids and Eicosanoids: Potential Effects on the Modulation of Inflammatory and Immune Cells: An Overview", Nutrition 6(1990)S24-S44.

JW Konturek, H Fischer, IR VanderVoort, W Domschke, "Disturbed gastric motor activity in patients with human immunodeficiency virus infection", Scand J Gastroent 32:1997:221-225.

JT La Brooy, "Enteropathy in HIV Infection", JAIDS 6:1993:S16-S19.

DF Lehmann, PD Holohan, DC Blair, "Comparisons of oxidative metabolism and reductive capacity in sulfonamide-tolerant and -intolerant patients with human immunodeficiency virus", J Clin Pharmacol 36:1996:1149-1153.

IT Mak, R Stafford, WB Weglicki, "Loss of red blood cell glutathione during Mg deficiency: Prevention by vitamin E, D-propranolol, and chloroquine", Am J Physiol - Cell Physiol 36:1994:C1366-C1370.

E Mayatepek, K Becker, B Carlsson, A Larsson, GF Hoffmann, "Deficient Synthesis of Cysteinyl Leukotrienes in Glutathione Synthetase Deficiency", Internat J Tissue Reactions - Experimental and Clinical Aspects 15:1993:245-252.

JP Merin, M Matsuyama, T Kira, M Baba, T Okamoto, "alpha-Lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants", FEBS Lett 394:1996:9-13.

A Meyer, R Buhl, H Magnussen, "The Effect of Oral Nacetylcysteine on Lung Glutathione Levels in Idiopathic Pulmonary Fibrosis", Eur Resp J 7:1004:431-436.

A Meyer, R Buhl, S Kampf, H Magnussen, "Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals", Amer J Resp Crit Care Med 152:1995:1055-1060.

S Mihm, D Galter, W Droge, "Modulation of transcription factor NF kappa B activity by intracellular glutathione levels and by variations of the extracellular cysteine supply", FASEB J 9:1995:246-252.

F Müller, AM Svardal, P Aukrust, RK Berge, PM Ueland, SS Frøland, "Elevated plasma concentration of reduced homocysteine in patients with human immunodeficiency virus infection", Am J Clin Nutr 63:1996:242-248.

BL O'Dell, "Cysteine-Rich Intestinal Protein (CRIP): A New Intestinal Zinc Transport Protein", Nutrition Reviews 50:1992:232-233.

MK Offermann, J-C Lin, E-C Mar, R Shaw, J Yang, RM Medford, "Antioxidant-Sensitive Regulation of Inflammatory-Response Genes in Kaposi's Sarcoma Cells", JAIDSHR 13:1996:1-11.

R Olivier, O Lopez, M Mollereau, T Dragie, D Geutard, L Montagnier, "Prevention of early cell death in peripheral blood lymphocytes of HIV infected individuals by an antioxidant: N-acetylcysteine", abstract, Conference on Oxidative Stress in HIV/AIDS - A Potential for Therapies, NIH, Maryland, Nov 8-10, 1993).

M Ott, B Lembcke, H Fischer, R Jäger, H Polat, H Geier, M Rech, S Staszeswki, EB Helm, WF Caspary, "Early Changes of Body Composition in Human Immunodeficiency Virus-infected Patients: Tetrapolar Body Impedance Analysis Indicates Significant Malnutrition", Am J Clin Nutr 57:1993:15-19.

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Author, Chester Myers, holds both honours B.Sc. and M.Sc. (1969) degrees in physical chemistry from Dalhousie University, and a Ph.D. (1975) from the University of Toronto (biophysical chemistry) where he investigated the mechanism of action of one of the digestive enzymes. In addition to publishing in the scientific literature and having authored several patents, he has written extensively on topics regarding health and HIV. The latter include articles in The Positive Side, Canadian AIDS News, and monographs available from the AIDS Committee of Toronto (ACT), the Community AIDS Treatment Information Exchange (CATIE), and various other organizations.

Disclaimer:
The material in this publication is for information purposes only. It does not endorse any particular treatment program nor strategy; neither is it intended as medical advice nor as a replacement for medical advice.

©This document is copyrighted by Chester Myers. All materials may be reprinted and/or distributed without prior permission. However, reprints may not be edited.

June 1997
Last modified on: 09/15/2004

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