Abstract
In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-l-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov, NCT00910442).
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References
Angelini G, Gardella S, Ardy M et al (2002) Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc Natl Acad Sci USA 99:1491–1496. https://doi.org/10.1073/pnas.022630299
Badaloo A, Reid M, Forrester T et al (2002) Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition. Am J Clin Nutr 76:646–652. https://doi.org/10.3945/ajcn.111.024323.INTRODUCTION
Bogden JD, Kemp FW, Han S et al (2000) Status of selected nutrients and progression of human immunodeficiency virus type 1 infection. Am J Clin Nutr 72:809–815
Borges-Santos MD, Moreto F, Pereira PCM et al (2012) Plasma glutathione of HIV+ patients responded positively and differently to dietary supplementation with cysteine or glutamine. Nutrition 28:753–756. https://doi.org/10.1016/j.nut.2011.10.014
Burini RC, Moreto F, Borges-Santos MD, Yu YM (2013) Plasma homocysteine and thiol redox states in HIV+ patients. In: McCully K (ed) Homocysteine: biosynthesis and health implications, 1st edn. Nova Science, New York City, pp 151–164
Burini RC, Borges-Santos MD, Moreto F, Yu YM (2015) Plasma antioxidants and glutamine supplementation in HIV. In: Rajendram R, Preedy V, Patel V (eds) Glutamine in clinical nutrition, Nutrition and health. Humana Press, New York
Burini RC, Borges-Santos MD, Moreto F, Ming-Yu Y (2018) Taurine and oxidative stress in HIV. In: Preedy V, Watson RR (eds) HIV/AIDS: Oxidative stress and dietary antioxidants. Elsevier, Amsterdam, pp 170–179
Di Giuseppe D, Ulivelli M, Bartalini S et al (2010) Regulation of redox forms of plasma thiols by albumin in multiple sclerosis after fasting and methionine loading test. Amino Acids 38:1461–1471. https://doi.org/10.1007/s00726-009-0350-8
Dröge W, Breitkreutz R (1999) N-acetyl-cysteine in the therapy of HIV-positive patients. Curr Opin Clin Nutr Metab Care 2:493–498. https://doi.org/10.1097/00075197-199911000-00011
Dröge W, Holm E (1997) Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB J 11:1077–1089
Dröge W, Eck HP, Gmünder H, Mihm S (1991) Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med. https://doi.org/10.1016/0002-9343(91)90297-B
Fermo I, D’Angelo SV, Paroni R et al (1995) Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med 123:747–753
Fukagawa NK (2006) Sparing of methionine requirements: evaluation of human data takes sulfur amino acids beyond protein. J Nutr 136:1676s–1681s
Garlick PJ (2006) Toxicity of methionine in humans. J Nutr 136:1722S–1725S
Griffith OW (1987) Mammalian sulfur amino acid metabolism: an overview. Methods Enzymol 143:366–376
Grimble RF (2005) Immunonutrition. Curr Opin Gastroenterol 21:216–222. https://doi.org/10.1097/01.mog.0000153360.90653.82
Jackson AA, Gibson NR, Lu Y, Jahoor F (2004) Synthesis of erythrocyte glutathione in healthy adults consuming the safe amount of dietary protein. Am J Clin Nutr 80:101–107
Jones DP (2004) Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control. FASEB J. https://doi.org/10.1096/fj.03-0971fje
Jones CY, Tang AM, Forrester JE et al (2006) Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort. J Acquir Immune Defic Syndr 43:475–482. https://doi.org/10.1097/01.qai.0000243096.27029.fe
Kozich V, Kraus E, De Franchis R et al (1995) Hyperhomocysteinemia in premature arterial disease: examination of cystathionine β-synthase alleles at the molecular level. Hum Mol Genet 4:623–629. https://doi.org/10.1093/hmg/4.4.623
Lanzillotti JS, Tang AM (2005) Micronutrients and HIV disease: a review pre- and post-HAART. Nutr Clin Care 8:16–23
Lyons J, Rauh-Pfeiffer A, Yu YM et al (2000) Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci USA 97:5071–5076. https://doi.org/10.1073/pnas.090083297
Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263:17205–17208
Nguyen D, Hsu JW, Jahoor F, Sekhar RV (2014) Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIV-infected patients. J Clin Endocrinol Metab 99:169–177. https://doi.org/10.1210/jc.2013-2376
Paroni R, De Vecchi E, Cighetti G et al (1995) HPLC with o-phthalaldehyde precolumn derivatization to measure total, oxidized, and protein-bound glutathione in blood, plasma, and tissue. Clin Chem 41:448–454
Patrick L (2000) Nutrients and HIV: part three—N-acetylcysteine, alpha-lipoic acid, l-glutamine, and L-carnitine. Altern Med Rev 5:290–305
Qureshi GA, Qureshi AR (1989) Determination of free amino acids in biological samples: Problems of quantitation. J Chromatogr Biomedical Appl 491:281–289
Radtke KK, Coles LD, Mishra U et al (2012) Interaction of N-acetylcysteine and cysteine in human plasma. J Pharm Sci 101:4653–4659. https://doi.org/10.1002/jps.23325
Raftos JE, Whillier S, Chapman BE, Kuchel PW (2007) Kinetics of uptake and deacetylation of N-acetylcysteine by human erythrocytes. Int J Biochem Cell Biol 39:1698–1706. https://doi.org/10.1016/j.biocel.2007.04.014
Rose WC (1938) The nutritive significance of the amino acids. Physiol Rev 18:109–136
Sbrana E, Paladini A, Bramanti E et al (2004) Quantitation of reduced glutathione and cysteine in human immunodeficiency virus-infected patients. Electrophoresis 25:1522–1529
Sekhar RV, Patel SG, Guthikonda AP et al (2011) Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr 94:847–853. https://doi.org/10.3945/ajcn.110.003483
Stipanuk MH (2004) Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr 24:539–577. https://doi.org/10.1146/annurev.nutr.24.012003.132418
Tousoulis D, Antoniades C, Marinou K et al (2008) Methionine-loading rapidly impairs endothelial function, by mechanisms independent of endothelin-1: evidence for an association of fasting total homocysteine with plasma endothelin-1 levels. J Am Coll Nutr 27:379–386
Triguero A, Barber T, García C et al (1997) Liver intracellular l-cysteine concentration is maintained after inhibition of the trans-sulfuration pathway by propargylglycine in rats. Br J Nutr 78:823–831 (S0007114597001852 [pii])
Ubbink JB, Hayward Vermaak WJ, Bissbort S (1991) Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 565:441–446
van der Griend R, Biesma DH, Banga JD (2002) Postmethionine-load homocysteine determination for the diagnosis hyperhomocysteinaemia and efficacy of homocysteine lowering treatment regimens. Vasc Med 7:29–33. https://doi.org/10.1191/1358863x02vm407ra
Viñ JR, Giménez A, Corbacho A et al (2001) Blood sulfur-amino acid concentration reflects an impairment of liver transsulfuration pathway in patients with acute abdominal inflammatory processes. Br J Nutr 85:173–178. https://doi.org/10.1079/BJN2000237
Zhou J, Coles LD, Kartha RV et al (2015) Intravenous administration of stable-labeled N-acetylcysteine demonstrates an indirect mechanism for boosting glutathione and improving redox status. J Pharm Sci 104:2619–2626. https://doi.org/10.1002/jps.24482
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To the Brazilian institutions FAPESP and CNPq for the research funding and fellowships.
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Burini, R.C., Borges-Santos, M.D., Moreto, F. et al. Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls. Amino Acids 50, 569–576 (2018). https://doi.org/10.1007/s00726-018-2538-2
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DOI: https://doi.org/10.1007/s00726-018-2538-2