NAC and Glutathione: Recent Publications.

We were surprised to learn how much work has been published recently on glutathione blood level, oxidative stress, and/or NAG or similar treatments to correct abnormally low glutathione, in various illnesses including HIV infection. Here are some of the papers that have been published in 1998, 1999, and 2000, listed alphabetically by first author. Quotes are from the authors' abstracts; comments in brackets are ours.

We collected these references so that researchers and physicians can quickly see how much new information exists. NAC should no longer be relegated only to "alternative" treatments, but deserves serious research as a possible addition to mainstream HIV therapy.

* Aaseth J and Stoa-Birketvedt G. Glutathione in overweight patients with poorly controlled type 2 diabetes. Journal of Trace Elements in Experimental Medicine. 2000; volume 13, number 1, pages 105-111. "Therapeutic trials with antioxidants that can regenerate the intracellular level of GSH [glutathione] are scarce but promising."

* Barditch-Crovo P, Noe D and others. A phase I/II evaluation of oral L-2-oxothiazolidine-4-carboxylic acid in asymptomatic patients infected with human immunodeficiency virus. Journal of Clinical Pharmacology. 1998; volume 38, number 4, pages 357-363. "After 4 weeks of administration [of Procysteine, also called OTC, which, like NAC, is used to supply cysteine] three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3000 mg dose groups compared with the placebo group."

* Behr J, Maier K and others. Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation. Transplantation. 2000; volume 69, number 9, pages 1856-1860. "Reduced glutathione was positively correlated with forced expiratory volume... We conclude that excessive oxidative stress and a lack of glutathione are associated with BOS after H/LTX and may play relevant roles in the development of this disorder."

* Ben-Menacherm E, Kyllerman M, and others. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Research. 2000; volume 40, number 1, pages 33-39. "NAG improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2."

* Breitkreutz R, Holm S, and others. Massive loss of sulfur in HIV infection. AIDS Research and Human Retroviruses. 2000; volume 16, number 3, pages 203-209. "The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool."

* Breitkreutz R, Pittack N and others. Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials. Journal of Molecular Medicine. 2000; volume 78, number 1, pages 55-62. "Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency. Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetylcysteine [NAC] treatment may be recommended for patients with and without antiretroviral therapy. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination."

* Choi J, Leu RM, and others. Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. Journal of Biological Chemistry. 2000; volume 275, number 5, pages 3693-3698.

* De Mattia G, Bravi MC, and others. Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus. Metabolism. 1998; volume 47, number 8, pages 993-997. "Intravenous GSH [glutathione] infusion significantly increased both intraerythrocytic GSH/GSSG ratio and total glucose uptake in the same patients."

* De Mattia G, Bravi MC and others. Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipideaemic, normotensive, patients with non-insulin-dependent diabetes. Diabetologia. 1998; volume 41, number 11, pages 1392-1396. "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."

* De Rosa SC, Zaretsky MD, Dubs JG, and others. N-acetylcysteine replenishes glutathione in HIV infection. European Journal of Clinical Investigation. 2000; volume 30, pages 841-856. [See article in this issue.]

* Dincer Y, Akcay T, and others. Erythrocyte susceptibility to lipid peroxidation in patients with coronary atherosclerosis. Acta Medica Okayama. 1999; volume 53, number 6, pages 259-264. "The levels of plasma high-density lipoproteins, vitamin C, vitamin E and erythrocyte GSH [glutathione] were significantly lower...in the patients with coronary atherosclerosis than in the controls."

* Engelen MP, Schols AM, and others. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. American Journal of Respiratory and Critical Care Medicine. 2000; volume 161, number 1, pages 98-103. "This study illustrates that reduced glutamate levels in skeletal muscle of patients with emphysema are possibly related to an enhanced glycolytic activity and associated with decreased glutathione levels."

* Estensen RD, Levy M, and others. N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyp. Cancer Letter. Volume 147, number 1-2, pages 109-114. "Since this decrease in proliferative index may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted."

* Gillissen A and Nowak D. Characterization of N-acetylcysteine and ambroxol in antioxidant therapy. Respiratory Medicine. 1998: volume 92, number 4, pages 609-623. "This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of antioxidant augmentation therapy to the lung by using NAC or ambroxol."

* Graber R, Farine JC, and others. Apoptosis and oxidative status in peripheral blood mononuclear cells of diabetic patients. Apoptosis. 1999; volume 4, number 4, pages 263-270.

* Gringhuis SI, Leow A, and others. Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis. Journal of Immunology. 2000; volume 164, number 4, pages 2170-2179.

* Holt S, Goodler D, and others. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet. 1999; volume 353, number 9149, pages 294-295.

* Jahoor F, Jackson A, and others. Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. American Journal of Physiology Endocrinology and Metabolism. 1999; volume 39, number 1, pages E205-E211. "Cysteine supplementation [by one week of NAC given to HIV-infected volunteers] elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte glutathione. These results suggest that the glutathione deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage of cysteine availability."

* Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: A critical review. Journal of Toxicology -- Clinical Toxicology. 1998; volume 36, number 4, pages 277-285.

* Kelly FJ. Glutathione: in defense of the lung. Food Chemistry Toxicology. 1999; volume 37, number 9-10, pages 963-966. "...new findings are beginning to reveal the role that the RTLF [respiratory tract lining fluid] glutathione pool plays in defending the lung."

* Lauterburg BH and Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut. 1998; volume 29, pages 1153-1157. "The data indicate that low glutathione may be a risk factor for [acetaminophen] hepatotoxicity in alcoholics because a lower dose of [acetaminophen] will be necessary to deplete glutathione below the critical threshold concentration where hepatocellular necrosis starts to occur."

* Malorni W, Rivabene R, and others. The role of oxidative imbalance in progression to AIDS: Effect of the thiol supplier N-acetylcysteine. AIDS Research and Human Retroviruses. 1998; volume 14, number 17, pages 1589-1596. "Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial."

* Miralles-Barrachina O, Savoye G, and others. Low levels of glutathione in endoscopic biopsies of patients with Crohn's colitis: the role of malnutrition. Clinical Nutrition. 1999; volume 18, number 5, pages 313-317. "Glutathione depletion may be related in part to malnutrition and contribute to a prolonged evolution of disease and could be a target for pharmacological and nutritional support." (Copyright 1999 Harcourt Publishers Ltd.)

* Moss M, Guidot DM, and others. The effects of chronic alcohol abuse on pulmonary glutathione homeostatis. American Journal of Respiratory and Critical Care Medicine. 2000; volume 161, number 2, pages 414-419. "This is the first report that chronic alcohol abuse alters glutathione homeostasis in the human lung, and suggests a potential mechanism by which chronic alcohol abuse predisposes susceptible patients to develop ARDS [acute respiratory distress syndrome].

* Opalenik SR, Ding Q, and others. Glutathione depletion associated with the HIV-1 Tat protein mediates the extracellular appearance of acidic fibroblast growth factor. Archives of Biochemistry and Biophysics. 1998; volume 351, number 1, pages 17-26. "Collectively, these results suggest that HIV-1 Tat induces a condition of oxidative stress, which mediates cellular secretion of FGF-1, an observation relevant to the pathophysiologic development and progression of AIDS-associated Kaposi's sarcoma."

* Prasad A, Andrews NP, and others. Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. Journal of the American College of Cardiology. 1999; volume 34, number 2, pages 507-514. "Thiol supplementation with glutathione selectively improves human endothelial dysfunction by enhancing NO (nitric oxide) activity." (Copyright 1999 by the American College of Cardiology.)

* Redondo P and Bauza A. Topical N-acetylcysteine for lamellar ichthyosis. Lancet. 1999; volume 354, number 9193, page 1880.

* Reid M, Badaloo A, and others. In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition. American Journal of Physiology Endocrinology and Metabolism. 2000; volume 278, number 3, pages E405-E412. "These results confirm that GSH deficiency is characteristic of edematous PEM [protein-energy malnutrition] and suggest that this is due to a reduced rate of synthesis secondary to a shortage in cysteine."

* Samiec PS, Drews-Botsch C, and others. Glutathione in human plasma: Decline in association with aging, age-related macular degeneration, and diabetes. Free Radical Biology & Medicine. 1998; volume 24, number 5, pages 699-704.

* Sido B, Hack V, and others. Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease. Gut. 1998; volume 42, number 4, pages 485-492. "As the impaired mucosal antioxidative capacity may further promote oxidative damage, glutathione deficiency might be a target for therapeutic intervention in IBD [inflammatory bowel disease]."

* Spapen H, Zhang HB, and others. Does N-acetyl-L-cysteine influence cytokine response during early human septic shock? Chest. 1998; volume 113, number 6, pages 1616-1624.

* Venturaq P, Panini R, and others. N-acetylcysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion. Pharmacological. Research. 1999; volume 40, number 4, pages 345-350.

* Vita JA, Frei B, and others. L-2-oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease. Journal of Clinical Investigation. 1998; volume 101, number 6, pages 1408-1414. "Cellular redox state...is a potential target for therapy in patients with coronary artery disease."