10/23/10 8:11 PM The Effects of Sulfur Amino Acid Intake on Immune Function in Humans -- Grimble 136 (6): 1660S -- Journal of Nutrition Page 1 of 7 http://jn.nutrition.org/cgi/content/full/136/6/1660S This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grimble, R. F. Search for Related Content PubMed PubMed Citation Articles by Grimble, R. F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diets TOP ABSTRACT LITERATURE CITED © 2006 The American Society for Nutrition J. Nutr. 136:1660S-1665S, June 2006 Supplement: 5th Amino Acid Assessment Workshop: Session I The Effects of Sulfur Amino Acid Intake on Immune Function in Humans 1 Robert F. Grimble 2 Institute of Human Nutrition, School of Medicine, University of Southampton, Southampton SO16 7PX, UK 2 To whom correspondence should be addressed. E-mail: rfg1@soton.ac.uk. ABSTRACT No direct data exist on the influence of supranormal intakes of sulfur amino acids on immune function in humans. However 3 major products of sulfur amino acids, glutathione (GSH), homocysteine (Hcy), and taurine (Tau), influence, mainly, inflammatory aspects of the immune response in vitro and in vivo. Methionine intakes above 1 g/d transiently raise plasma Tau, Hcy, and GSH. Tau and GSH ameliorate inflammation. Hcy has the opposite effect. A biphasic relation, between cellular GSH and CD4 + and CD8 + numbers occurs in healthy men. How changes in sulfur amino acid intake influence this phenomenon is unknown. In animals, high Tau intakes are antiinflammatory. How immune function in humans is affected is unknown. A positive relation between plasma neopterin (a marker of a Th-1–type immune response) and Hcy indicates that Hcy may play a part in inflammatory aspects of Parkinson's disease and aging. In vitro, Hcy, at concentrations seen following consumption of 6 g L-methionine/d in adults, increases the interactions among T lymphocytes, monocytes, and endothelium. Whether a similar phenomenon occurs in vivo is unknown. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with raised plasma Hcy in young but not old subjects. The relation of this observation to immune function is unknown. The relationships among Hcy, inflammatory aspects of disease, and in vitro alterations in immune cell behavior create a cautionary note about supplementation of diets with L-methionine to raise intake above 1 g/d. Studies directly linking methionine intake, genetics, plasma Hcy, Tau, and GSH and immune function are needed. KEY WORDS: • methionine • cysteine • glutathione • homocysteine • immune function Sulfur amino acids and their chief metabolites are of major importance in health and disease. Methionine is classified as nutritionally essential. Cysteine is classified as semiessential due the variable capacity of the body for its production from methionine. The metabolic pathway between the 2 amino acids contains the intermediate homocysteine (Hcy). 3 Hcy synthesis is influenced by B-vitamin intake (folic acid, vitamins B-6 and B-12) and functional single-nucleotide polymorphisms that influence folate metabolism ( 1– 3). Sulfate and taurine are the major endproducts of sulfur amino acid metabolism. The immune system, in its actions against invading organisms, involves a complex interrelated series of cellular and metabolic activities. The important question, therefore, is how variations in tissue availability of sulfur amino acids and the products of their metabolism interact with these processes. Clearly, a sufficient metabolic supply of sulfur amino acids from diet and tissue protein breakdown is necessary for the synthesis of the myriad of proteins and peptides involved in normal functioning of the immune system. The impact of a high sulfur amino acid intake on immune function has not been investigated in any depth in humans or experimental animals. Many studies have examined the effects of high intakes of methionine and cysteine on growth and mortality in rodents, chiefly rats (e.g., 4). A limited number of studies on the impact of alterations in dietary sulfur amino acid intake on the inflammatory process have also been conducted in rats ( 5). In humans, the pioneering work of Young's group examined metabolic effects of increasing sulfur amino acid intake, to approximately double the requirement for methionine plus cysteine ( 6). No measures of immune function were reported in these investigations. Nonetheless a number of studies have reported the effects of metabolic products of sulfur amino acids [Hcy, taurine (Tau), glutathione (GSH)] in in vitro studies on various functions of human immune cells. Research in clinical nutrition has focused on the effects of sulfur amino acid precursors such as N-acetyl cysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (OTC), on various aspects of human immune function. Because cysteine is unstable in its reduced form, is toxic in high doses, and is mostly degraded in the extracellular compartment, OTC and NAC have been used to deliver cysteine directly to cells. OTC is an analog of 5-oxoproline in which the 4-methylene moiety has been replaced with sulfur. It provides an excellent substrate for 5-oxoprolinase (an intracellular enzyme). The enzyme converts OTC to S-carboxy- L-cysteine, which is rapidly hydrolyzed to L-cysteine.