Micronutrient Study - Background Information

Research Project:
Micronutrient Study - Backround Information on Integrative Health Consulting Protocol #1001

Research on broad-spectrum micronutrient supplementation, instead of testing one nutrient per study, is based on the interdependence of the mammalian mitochondria on multiple nutrients for healthful functioning. Ascorbate (vitamin C), alpha-tocopherol (vitamin E), alpha-lipoic acid, and glutathione (from N-acetyl cysteine) are dependent upon each other to replenish their lower valence, bio-active moieties subsequent to oxidation by free radicals. Supplementing only one of these nutrients does not make biochemical sense if the goal is to promote improved functioning of a dysfunctional Kreb's cycle and electron transport system.

The therapeutic supplementation of the antioxidant nutrients described below holds promise as adjunctive therapy in the treatment of HIV disease. As a class, these antioxidants enhance T and B lymphocyte proliferation, decrease the release of lactic acid into the bloodstream, and enhance mitochondrial energy production.^[1] These effects may also be beneficial for preventing cell apoptosis, which occurs secondary to the increased oxidative stress found in HIV infection (with or without nucleoside reverse transcription inhibitor therapy).^[2],^[3]

In addition, nucleoside reverse transcriptase inhibitors are known to inhibit mitochondrial gamma DNA-polymerase.^[4],^[5] The resultant depletion of mitochondrial DNA may contribute to a dysregulation of the cytochrome energy system of the electron transport chain. This functional uncoupling of oxidative metabolism creates a backup of acetyl Co-enzyme A, as well as lactic acid, both intracellularly and extracellularly. The release of these compounds into the blood leads to an increase in gluconeogenesis in the liver thereby producing increased serum insulin levels and concomitant hyperlipidemia.^[6] These physiologic effects may contribute to an increase in truncal fat accumulation in HIV-infected patients. This process is commonly described as HIV-associated lipodystrophy syndrome.

The acetyl moiety of the amino acid carnitine regulates fatty acid transport across the mitochondrial membrane. It also functions to provide this organelle with fuel which enhances its ability to produce energy under anaerobic conditions. Anaerobic metabolism is more likely to occur if the electron transport chain is dysregulated due to a depletion of mitochondrial DNA. In prior studies, acetyl L-carnitine has been used successfully as a treatment for mitochondrial myopathy, a recognized side effect of nucleoside reverse transcriptase inhibitors such as zidovudine (AZT).^[7],^[8]

Frank acetyl L-carnitine deficiency has also been shown to be present in a significant percentage of HIV-infected individuals diagnosed with peripheral neuropathy.^[9] In small studies, supplementation with this nutrient alone has been successful in reversing the peripheral neuropathy seen in both diabetes mellitus and HIV disease.^[10]

Alpha-lipoic acid is a potent antioxidant found primarily in the mitochondria. It acts as a coenzyme in the alpha-keto-dehydrogenase enzyme complex of the Kreb's cycle to facilitate aerobic respiration. It also functions as a potent free radical scavenger whose actions help to maintain healthful mitochondrial functioning. This compound also participates in the metabolic pathways which regenerate de novo levels of ascorbate, alpha-tocopherol, and glutathione.

Alpha-lipoic acid has been shown to directly block NF-kappa B activation, to directly inhibit HIV replication in cell cultures, and to successfully treat peripheral neuropathy in patients with diabetes mellitus.^[11],^[12] In a small German study, alpha-lipoic acid was shown to increase the number of CD4 cells and the CD4:CD8 ratio in HIV-infected patients.^[13]

The acetyl moiety of the amino acid cysteine is the most bioavailable oral source of glutathione. Glutathione is a potent antioxidant and a key component of the glutathione peroxidase enzyme system. Glutathione deficiency has been associated with a poor prognosis in HIV disease.^[14],^[15]

There is also reason to believe that Tat, a protein produced by HIV, may be responsible for reducing glutathione levels in HIV-infected cells.^[16] There is additional evidence that nucleoside reverse transcriptase inhibitors (AZT,D4T,DDI, etc.) may directly decrease glutathione levels. These possible medication toxicities might be lessened by a restoration of glutathione levels to normal by the administration of NAC.

Studies published during the past five years by Stanford researchers Leonard and Leonore Herzenberg and their colleagues strongly suggest that 1) glutathione deficiency is common in HIV-infected patients ^[17] 2) glutathione deficiency in HIV-infected patients is associated with impaired T-cell function as well as impaired survival ^[18] 3) N-acetyl cysteine administration taken in oral form replenishes glutathione levels in HIV-infected patients, ^[19],^[20] and 4) N-acetyl cysteine administration in HIV-infected patients is significantly associated with improved 2-3 year survival in a Cox Proportional Hazards Analysis.^[21]

The purpose of the RDA for vitamin and mineral intake is to promote normal health and eliminate nutrient deficiency diseases in otherwise healthy adults.

The literature contains many references which suggest that, for the treatment of peripheral neuropathy, higher than normal intake of several key micronutrients (i.e. alpha-lipoic acid, vitamin B6, acetyl L-carnitine) have been effective in reversing the symptoms of this condition.^[22],^[23]

By utilizing dosages above the RDA, it may be possible to prevent, as well as therapeutically reverse, mild toxicities due to antiviral medication in a relatively brief period of time.

^[1] Kalebic T, et al. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetyl cysteine. Proc Natl Acad Sci USA 1991;88:986-990

^[2] Butte TM, et al. Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:7-10

^[3] Sato N, et al. Thiol-medicated redox regulation of apoptosis. Possible roles of cellular thiols other than glutathione in T cell apoptosis. J Immunol. 1995;154:3194-3203

^[4] Parker WB, et al. Mitochondrial toxicity of antiviral nucleoside analogs. J NIH Res. 1994;6:57-61

^[5] Chen CH, et al. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency compound 2',3'-dideoxycytidine. J Biol Chem. 1989;264:11934-11937

^[6] Khouri S, et al. Lactic acidosis secondary to nucleoside analog antiretrovial therapy. Infec Med. 2000;17[8]:547-554

^[7] Campos Y, et al. Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy. Muscle Nerve. 1993;16:150-153

^[8] Dalakas MC, et al. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol. 1994;35:482-487

^[9] Famularo, et al. Acetyl carnitine deficiency in distal polyneuropathy. AIDS 1997;11:185

^[10] Famularo G, et al. Treatment with acetyl-L-carnitine has the potential to improve the clinical course of painful peripheral neuropathies in HIV-positives patients. J Peripher Nerv Syst.1998; 3 (3) :227-9

^[11] Packer L, et al. Vitamin E and alpha-lipoate: role in antioxidant recycling and activation of the NF-kappa B transcription factor. Mol Aspects of Med 1993;14:229-239

^[12] Baur A, et al. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Klin Wochenschr 1991;69:722-724

^[13] Fuchs J, et al. Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients. Arzneimittelforschung 1993;43:1359-1362

^[14] Aukrust P, et al. Glutathione redox disturbances in human immunnodeficiency virus infection: immunologic and therapeutic consequences. Nutrition 1999;15:165-167

^[15] De Quay B, et al. Glutathione depletion in HIV-infected patients:role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992;6:815-819

^[16] Choi J, et al. Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. Journal of Biological Chemistry. 2000;275[5];3693-3698

^[17] Buhl R, et al. Systemic glutathione deficiency in symptom free HIV-seropositive individuals. Lancet. 1989;2:1294-1298

^[18] Herzenberg LA, et al. Glutathione deficiency is associated with impaired survival in HIV disease.. Proceedings of the National Academy of Sciences, USA . 1997;94:1967-1972

^[19] De Quay B, et al. Glutathione depletion in HIV-infected patients:role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992;6:815-819

^[20] Witschi A, et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43:667-669

^[21] Herzenberg LA, et al. Glutathione deficiency is associated with impaired survival in HIV disease.. Proceedings of the National Academy of Sciences, USA . 1997;94:1967-1972

^[22] Scarpini E, et al. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst. 1997; 2 (3) :250-252

^[23] Abbas ZG, et al. Evaluation of the efficacy of thiamine and pyridoxine in the treatment of symptomatic diabetic peripheral neuropathy. East Afr Med J. 1997 Dec; 74 (12) :803-8