Adverse effects

Abstract

The adverse effects of amino acids in humannutrition and health have been reviewed inthe context of the classical categories ofimbalance, antagonism, and toxicity, firstestablished in studies with animal models.This system has long existed as a conceptualframework primarily confined within theacademic domain. However, there is nowenhanced awareness that these categoriesmay be relevant to a greater or lesser extentin human nutrition and health. A number ofconclusions emerge in the light of this analysis,as detailed below.It is suggested that two subdivisions,namely 'clinical amino acid imbalance' and'excitotoxicity', are required within this classificationto more accurately reflect observationsin humans.Clinical amino acid imbalance appearsto be a regular feature of specific diseaseconditions. In patients with septic encephalopathyor with chronic liver disease, plasmaratios of branched-chain to aromatic aminoacids are consistently reduced. Abnormalplasma amino acid patterns may also be seenin patients with cancer, cystinuria andHuntington's disease.It is proposed that the category ofantagonisms should include the effects of awide range of plant non-protein aminoacids. Canavanine, homoarginine andindospicine share structural similarity andcompete with arginine for cellular transportand in the modulation of nitric oxide synthesis.Selenium analogues of the sulphuramino acids act by competing with methionineand cysteine at the levels of transportand protein synthesis. b-N-Oxalylamino-Lalanineand b-N- methylamino-L-alanine arepotent glutamate receptor agonists implicated,respectively, in neurolathyrism and inamyotrophic lateral sclerosis andParkinsonism-dementia (or Guam dementia).However, the aetiology of Guamdementia remains under review. On theother hand, it is widely acknowledged thathypoglycin A is associated with the seasonalincidence of a specific condition known as'vomiting sickness'.The category of toxicity is of particularsignificance in human health as it includes theadverse effects of glutamate, homocysteine,modified lysine residues and phenylalanine.The human health implications of these aminoacids are reviewed later in this volume.Glutamate is the principal excitatory aminoacid implicated in neurodegenerative disorders.Thus, the status of excitotoxicity as thesecond significant subdivision in the classificationof adverse effects of amino acids isamply justified.Despite the adverse health implicationscited above, there is increasing evidence thatimbalance may be adapted for clinical purposes.In several studies, acute imbalancehas been induced by the administration ofdrinks or mixtures rich in the indispensableamino acids but devoid of tryptophan ortyrosine and phenylalanine. This techniquethus conforms with the classical method ofprecipitating amino acid imbalance. Theresulting reductions in concentrations of therespective neurotransmitters provide a metabolicbasis for psychiatric investigations.The potential of amino acid imbalance incancer therapy has been briefly reviewed.The emerging consensus relates to the efficacyof branched-chain amino acid depletionin the inhibition of tumours in experimentalmodels. However, the potential scope forspecific non-protein amino acids in cancertherapy appears to be relatively more promising.Varying degrees of success have beenreported with canavanine, sulphur aminoacid analogues and mimosine. In experimentalmodels, certain synthetic congenersof canavanine exhibit enhanced potential,but Se-methylselenocysteine is highly active,particularly in optimizing the therapeuticefficacy of anti-cancer drugs.The wide interpretation of 'adverseeffects' of amino acids adopted in this chapterthus allows a perspective for further considerationof clinical implications relating to cardiovascular,genetic and neurologicaldisorders. Appropriate cross-referencing tosubsequent chapters is provided for detailedreview of these conditions.group, amino acids provide the buildingblocks for the biosynthesis of tissue proteins,but individual members play equally vitalroles as signalling molecules ans orsof specific neurotransmitters, hormones,purines, pyrimidines, creatine, haem andpolyamines. Furthermore, arginine yieldsnitric oxide, while tryptophan is used to generatenicotinamide. Individual amino acidscannot be retained indefinitely as free moleculesand must proceed along these syntheticpathways or follow catabolic routes involvingdeamination and synthesis of urea. Theresidual carbon skeletons are metabolizedfurther in the processes of gluconeogenesisand/or ketogenesis. The metabolic fate ofamino acids is often encapsulated in theseterms in standard texts on biochemistry, andfor most intents and purposes such a synopsisis eminently acceptable. Within such abenign scenario it is tacitly assumed that anysurplus of amino acids is disposed of withoutharmful effects. However, this simplisticview is no longer tenable as increasinglymore evidence accumulates to demonstratethe adverse effects of amino acids in severalmammalian species, including humans.The adverse effects of amino acids arewell-established in studies with animals andthe results extensively documented andreviewed (Harper, 1959; Harper et al., 1970;D'Mello, 2003). The literature relating to thisfield is in a reasonably advanced state. Thereare now compelling reasons to review theexpanding evidence that these adverse effectsmay be replicated, to different degrees, inhuman subjects. The terminology developedwith animal models is finding common usagein clinical sciences and it is opportune toexamine the relevant data within the contextof existing evidence.© CAB International 2012.