The morning of the first day of the 8th Amino Acid Assessment Workshop was organized and co-sponsored by the International Council on Amino Acid Science (ICAAS) and the International Life Sciences Institute Research Foundation and was focused on the International Life Sciences Institute Research Foundation's approach to establishing upper limits of nutrients. The remainder of d 1 and all of d 2 were focused on the safety of leucine and tryptophan, with special emphasis on determining the upper level of the safe range of intake. It was recognized that some toxicological frameworks, mainly the key-events dose response framework, might be applicable to amino acids and provide appropriate assistance to regulators in establishing upper limits for amino acids as a group of nutrients used in dietary supplements. ICAAS-funded projects for determining the upper intake limits for the essential amino acid leucine provided the main pool of leucine data discussed at the workshop. The acute clinical study suggests 500 mg/(kg ⋅ d) as a possible upper limit for leucine in healthy humans, but the safety margin needed to widen this limit to the general population has not been determined. For tryptophan, the workshop participants found less ground for consensus. Older efficacy studies suggested that tryptophan at 8-15 g/d was well tolerated, but human research was abruptly terminated in the late 1980s and no new data are available. Animal results obtained in pigs and rodents were discussed and 2 possible strategies for applying those outcomes to humans were described.
[Show abstract][Hide abstract] ABSTRACT: The cellular stress response can mediate cellular protection through expression of heat shock protein (Hsp70), which can interfere with the process of apoptotic cell death. Factors regulating renal epithelial cell apoptosis include angiotensin II. In the present study, we have examined the relationship between the Hsp70 expression and the apoptotic pathway in the kidneys from low-protein-fed rats (8% protein). The possible cytoprotective role of Hsp70 has been evaluated during low-protein feeding and after reincorporation of 24% protein in the diet. The effect of angiotensin II AT1 receptor inhibition has also been studied. Rats were fed with a low-protein (LP) diet (8% protein) for 14 days, and then the animals were recovered by means of a normal protein diet (24% protein) (RP) for 14, 21, and 30 days, and control rats received 24% protein (NP) in the diet. LP and NP rats treated with Losartan (10 mg/kg) were also evaluated. The following methods were performed on the kidneys: terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay for apoptosis, reverse transcriptase-polymerase chain reaction assay for AT1, Bax, and Bcl-2 messenger ribonucleic acid (mRNA) expression, and immunohistochemical and Western blot for Hsp70 and caspase 3 protein expression and activity. In the LP group, the cells of the medullary ducts (MDs) showed increased apoptosis associated with weak immunoreaction for Hsp70 and decreased Hsp70 protein levels. In these animals, enhanced proapoptotic ratio Bax/Bcl-2 linked to decreased procaspase 3 protein levels with increased caspase 3 activation were demonstrated. A cytoprotection attributed to Hsp70 could be noted in the RP rats after 21 days of reincorporation of the normal diet, and in the LP-fed group treated with Losartan. In these cases, the MD cells displayed decreased apoptosis and increased Hsp70 expression in colocalization staining, and high Hsp70 levels in cytosolic fraction. A decreased proapoptotic ratio Bax/Bcl-2, associated with increased Bcl-2 mRNA, was also observed. Our results provide evidence for an antiapoptotic, cytoprotective effect of Hsp70 in kidney MD cells of rats with LP intake, when the animals were recovered with 24% protein in diet and after angiotensin II AT1 receptor inhibition. Angiotensin II seems to play a role in the pathogenesis of tubule epithelial cell apoptosis during LP feeding.
[Show abstract][Hide abstract] ABSTRACT: The daily nutritional requirement for l-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting l-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the "serotonin syndrome" occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This is not surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted.
Journal of Nutrition 10/2012; 142(12). DOI:10.3945/jn.111.157065 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leucine's wide-ranging metabolic influences have made it subject to special interest. It is abundant in the diet, especially in some milk and cereal proteins, in part due to its allocation of 6 codons in the genetic code, and individual dietary intakes range up to >250 mg ⋅ kg(-1) ⋅ d(-1). It influences many cell functions by various mechanisms, which include allosteric activation of enzymes, enabling ATP generation and insulin secretion from the pancreatic islet cell, and activation of signaling pathways. It is a mediator of the anabolic drive of dietary amino acids, stimulating anabolic hormone secretion and directly signaling protein deposition and growth through the stimulation of protein synthesis and restraint of proteolysis. Its signaling may involve the mammalian target of rapamycin complex and rapamycin-insensitive pathways responding to a leucine "transceptor," which combines leucine cellular transport, fueled by the intracellular-extracellular glutamine gradient, and a signaling response to changes in ionic and water balance and cell volume. In animal studies, dietary leucine supplementation has reversed many of the adverse influences of a high-fat diet, consistent with a benefit for healthy weight maintenance in humans for which evidence is accumulating. The implications for safety of leucine-supplemented diets are discussed in terms of adversely lowering valine and isoleucine concentrations and inducing hyperammonemia through overloading peripheral glutamine synthetic pathways. Finally, the apparently high human leucine requirement is explained in terms of both an adaptive metabolic demand model of requirements and the design and analysis of human studies, which may overestimate values.
Journal of Nutrition 10/2012; 142(12). DOI:10.3945/jn.111.157370 · 3.88 Impact Factor
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