Two previous studies have shown that these central measures reached their lowest point approximately two hours after the onset of the maximal changes of plasma tryptophan measures for both the 50 g and g depletion formulations, and noted that this extended estimate does not account for time between brain changes and measurements taken at the lower end of the spinal column.
Relative to the other methods for experimentally reducing brain serotonin synthesis i. These amino-acid manipulations are economical, safe, and minimally invasive, as well as highly effective for rapidly producing substantial changes in tryptophan availability to the brain. These effects are also transient and quickly reversed by returning to a normal diet. For these reasons, acute tryptophan depletion has remained an important and popular research tool for understanding serotonergic dysregulation.
Acute changes in tryptophan availability have been used to test a wide variety of basic psychological, behavioral, and physical processes, 66 , including: motion sickness, sleep, , mood, 27 , 77 visual discrimination, 30 cognition, 34 social information processing, 33 and memory processes. One of the earliest and most common uses of tryptophan depletion was for the study of changes in mood which are commonly believed to be related to serotonergic mechanisms.
Some of the earliest studies found modest mood-lowering effects following acute tryptophan depletion in samples of healthy young men. The extent of the effects of acute tryptophan depletion on mood appears to be related to varying levels of vulnerability to disturbance of the central serotonin system.
Relative to healthy controls, there is more consistency of mood-lowering effects in healthy adults who may be vulnerable to serotonin disturbances, such as those with family histories of mood disorders 16 , 32 , , , or other underlying biological vulnerabilities e. In 8 out of 10 studies, tryptophan depletion produced a temporary return of clinical symptoms in patients who were responsive to their treatments.
These studies administered tryptophan depletion to symptom-free, treatment-free individuals with a history of either a major depressive episode or seasonal affective disorder, and followed the individuals for up to one year. Results from both studies indicated that the individuals who responded with depressive symptoms during tryptophan depletion were at greater risk for subsequent depressive episodes than non-responders. In summary, these results suggest that serotonin dysfunction is a trait abnormality in depressive disorders, and that individuals with a particular biological vulnerability for future depression may be especially sensitive to even transient changes in serotonin availability.
In contrast to the typical lack of mood changes in healthy adults, tryptophan depletion has been demonstrated to affect a variety of cognitive processes in both healthy individuals and those with a serotonergic vulnerability.
Impairments in a variety of learning and memory skills following tryptophan depletion are well documented. The most reliable findings are impairments of declarative episodic memory processes of delayed recall and memory consolidation. These long-term memory deficits in delayed recall have been replicated in numerous studies using a variety of presentations, including visual and auditory presentation of words, as well as presentation of pictures and abstract shapes for detailed reviews, see , These effects have been found in healthy adult volunteers, 31 , — in adults with a family history of bipolar disorder, and in clinical samples.
Tryptophan depletion has also been shown to impair learning on visual discrimination and memory retrieval, episodic memory, stimulus-reward learning, 30 and cognitive flexibility, among other cognitive processes, although more studies are needed to test the reliability of these results. In an editorial commentary on cognitive effects of tryptophan depletion, Riedel notes that there are a number of other physiological effects that may result from tryptophan manipulations that could be involved in the modulation of cognitive functions, such as quinolinic acid NMDA agonist , and kynurenic acid NMDA, nicotinic, and glutamatergic antagonist , which should also be considered for measurement.
Finally, tryptophan manipulations have a long history of studying behavior using laboratory-measures to assess social behavior and changes in aggression and impulsivity that may be dependent, in part, on changes of serotonin synthesis. Point Subtraction Aggression Paradigm, PSAP; , was shown to increase following tryptophan depletion, and this effect was greater in those that responded more aggressively before the manipulation. PSAP while tryptophan loading decreased aggression and this effect was specific to those women with elevated plasma tryptophan at baseline.
As noted in the previous study, this association was specific to women with elevated plasma tryptophan, compared to women with lower plasma tryptophan levels who were more agreeable, less hostile, and less likely to express their anger.
Both animal and human studies have shown that serotonin function is involved in inhibitory control of aggression. In another study of young men with and without a family history of paternal alcoholism, tryptophan depletion showed no effect on aggressive responses during a modified Taylor aggression task in either group.
A recent examination of whether serotonin modulates impulsive behavior through mechanisms involved in emotion used tryptophan depletion and placebo control to test a laboratory model of self-regulation.
Future studies that use multiple behavioral measures in the same experimental sample may clarify these conflicting findings. When examining the relationship of trait impulsivity to changes following tryptophan depletion, boys with ADHD were divided into high and low trait impulsivity groups. Using a competitive reaction time test, tryptophan depletion increased impulsive aggression of the low impulsive group, but not the high impulsive group. Additionally, using a continuous performance test in normal healthy men, tryptophan depletion produced increased laboratory-measured impulsivity compared to placebo.
Rather, increased serotonin impaired learning, whereas noradrenaline had no effect. This difference between continuous performance and stop-signal tasks may signify different underlying behavioral mechanisms governing these responses.
A recent review of brain activation in imaging studies i. The authors concluded that overall, results appear to indicate involvement of serotonin dysregulation in cognitive impairments, but the number of divergent results remains puzzling. Contrary findings from different studies may be the result of a variety of explanations and a host of methodological differences, including use of tasks that measure different underlying processes and testing samples of individuals who differ in personality, gender, family histories, and genetic vulnerabilities.
While serotonin plays a part in cognitive functions, inconsistencies across studies need to be addressed in the future both to control for, and study, interindividual differences. While dietary intake alone i. One of the earliest examples was an attempt by Lauer and colleagues to augment treatment response for schizophrenia by combining tryptophan administration with iproniazid, a monoamine oxidase inhibitor MAOI.
The success of the combined treatment compared to the MAOI alone changed how researchers thought about the influence of tryptophan treatment on brain function, 84 and began a series of clinical trials testing the efficacy of treatment for a number of clinical disorders that yielded promising but often inconclusive results. Tryptophan has also been widely used as an over-the-counter, natural remedy for depression, pain, insomnia, hyperactivity, and eating disorders. The therapeutic use of tryptophan for treatment of clinical disorders and syndromes has concentrated primarily on increasing tryptophan intake for the treatment of depressive disorders and related conditions, although other psychiatric and medical conditions appear to be somewhat responsive to tryptophan treatment.
One of the most frequent clinical uses of tryptophan has been for the treatment of major depression; however, clinical findings of the efficacy of tryptophan treatments are mixed. Tryptophan has been found to be as effective as tricyclic antidepressants in a number of trials, — and one study found that the effects of tryptophan and amitriptyline, alone and in combination, were all superior to placebo. Studies of tryptophan in combination with electroconvulsive therapy ECT have also produced inconsistent findings.
In contrast to the mixed results of the effects of tryptophan with tricyclic antidepressants or ECT, tryptophan has been shown to be more effective in combination with monoamine oxidase inhibitors MAOI. A significantly higher percentage of the patients on the combined therapy i. Although the results of the therapeutic combination of tryptophan with MAOIs have demonstrated the most successful results for treatment of depression, most clinical studies have produced mixed results as to the efficacy of tryptophan for treatment of depression.
These mixed results are due, in part, to flawed study designs and trials using insufficient lengths of time to allow determination of efficacy. Methodological differences such as inconsistent diagnostics within and across studies 43 have also produced mixed results. Taken together, there is evidence that tryptophan is effective for ameliorating mild to moderate depressive symptoms, but not severe depressive symptoms.
Tryptophan has been used successfully in the treatment of seasonal affective disorder and may be as effective as light therapy.
In one open-label study, 16 patients who met DSM-IV criteria for a recurrent major depressive disorder with a seasonal winter pattern were treated with light therapy for 2 weeks. Half received 2 weeks of light therapy first and the other half received 4 weeks of tryptophan treatment first with a 1-week washout between treatments.
While one third of the patients showed no response to either treatment, over half of the patients showed significant improvement during both treatments regardless of the order of treatment. These effects were thought to be the result of increased kynurenine synthesis during the late-luteal phase of the menstrual cycle.
Tryptophan has also been used for the treatment of sleep disorders, and is thought to produce its therapeutic effects through melatonin mechanisms. Improvement in sleep latency has been reported , with doses as low as 1 g, and improved Stage IV sleep has been reported with doses as low as mg. In summary, tryptophan is a unique amino acid that is an essential component of the human diet.
Although it has the lowest concentration in the human body relative to the other 19 primary amino acids, tryptophan is a critical component of numerous metabolic functions. Despite the side effects noted above and past concerns about the safety of tryptophan as a treatment or nutritional supplement, tryptophan has been widely used in numerous research and clinical trials without incident for nearly 25 years e.
To improve the utility of tryptophan research for understanding the relationship of serotonin dysregulation as an underlying mechanism in psychiatric disorders, as well as behavioral, cognitive, and physical problems, it will be important to understand the factors that have contributed to the inconsistent results from previous studies.
To advance the efficacy and utility of tryptophan for therapeutic purposes, future clinical studies will need to improve on methodological pitfalls made in the past. Such considerations would include employing systematic control of dosing, standardization of both research and treatment methodologies, and improved diagnostics of psychiatric disorders to test more homogeneous groups of patients, as well as careful selection and matching of patient and control groups or conditions being tested.
Dougherty gratefully acknowledges support from the William and Marguerite Wurzbach Distinguished Professorship. We thank Samantha E. John, B. National Center for Biotechnology Information , U. Int J Tryptophan Res. Published online Mar A Find articles by Ashley Acheson. Author information Copyright and License information Disclaimer.
Correspondence: Donald M. Dougherty, Ph. This article has been cited by other articles in PMC. Abstract An essential component of the human diet, L-tryptophan is critical in a number of metabolic functions and has been widely used in numerous research and clinical trials.
Keywords: L-tryptophan, depletion, loading, therapeutics, clinical uses, metabolism. Introduction Hopkins and Cole 1 discovered tryptophan in the early s after isolating it from casein protein, and Ellinger and Flamand 2 determined its molecular structure a short time later. Open in a separate window. The recommended daily allowance for a 79 kg lb adult is to mg.
Metabolic processes Protein synthesis The principal role of tryptophan in the human body is as a constituent of protein synthesis. Other metabolic functions Tryptophan also exerts effects on other neurotransmitters and CNS compounds. Pharmacokinetics Tryptophan is the sole precursor of serotonin 35 and, once consumed, tryptophan is distributed throughout the human body in the circulatory system.
Research Methodologies of Tryptophan Manipulation While there are a number of methodologies used to study serotonin dysregulation, one of the most widely used methods is to reduce brain serotonin synthesis, typically by reduction of tryptophan availability.
L -tryptophan Formulation 50 g g L -tryptophan Depletion 0. Effectiveness of tryptophan manipulations Using both tryptophan depletion and loading, many studies have provided measures of the effectiveness of these manipulations for changing plasma tryptophan. Methodological considerations When designing research protocols to investigate various mood, behavior, or cognitive effects of this methodology, it is important to consider that the onset and duration of the peak change in plasma indicators of brain serotonin synthesis likely do not coincide with serotonergic changes in the brain, which may affect the experimental design.
Research Applications of Acute Tryptophan Depletion Acute changes in tryptophan availability have been used to test a wide variety of basic psychological, behavioral, and physical processes, 66 , including: motion sickness, sleep, , mood, 27 , 77 visual discrimination, 30 cognition, 34 social information processing, 33 and memory processes. Mood and depression One of the earliest and most common uses of tryptophan depletion was for the study of changes in mood which are commonly believed to be related to serotonergic mechanisms.
Cognitive processes In contrast to the typical lack of mood changes in healthy adults, tryptophan depletion has been demonstrated to affect a variety of cognitive processes in both healthy individuals and those with a serotonergic vulnerability. Behavior Finally, tryptophan manipulations have a long history of studying behavior using laboratory-measures to assess social behavior and changes in aggression and impulsivity that may be dependent, in part, on changes of serotonin synthesis.
Therapeutic Uses of Tryptophan While dietary intake alone i. Depression Tryptophan has been found to be as effective as tricyclic antidepressants in a number of trials, — and one study found that the effects of tryptophan and amitriptyline, alone and in combination, were all superior to placebo.
Other mood disorders Tryptophan has been used successfully in the treatment of seasonal affective disorder and may be as effective as light therapy. Sleep disorders Tryptophan has also been used for the treatment of sleep disorders, and is thought to produce its therapeutic effects through melatonin mechanisms. Conclusions In summary, tryptophan is a unique amino acid that is an essential component of the human diet.
Acknowledgments Dr. Footnotes Disclosure The authors report no conflicts of interest. References 1. A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion.
J Physiol. Ellinger A, Flamand C. Uber syntetisch gewonnes tryptophan und einige seiner derivate. Precursor control of neurotransmitter synthesis.
Pharmacol Rev. Young VR. Adult amino acid requirements: The case for a major revision in current recommendations. J Nutr. L-tryptophan: Biochemical, nutritional and pharmacological agents.
Amino Acids. Stryer L. Kinetic analysis of blood-brain barrier transport of amino acids. Biochim Biophys Acta. Oldendorf WH. The blood-brain barrier. Exp Eye Res. Rapid depletion of plasma tryptophan: A review of studies and experimental methodology. J Psychopharmacol.
Young LS, Stoll S. Products containing soy, such as tofu, soya milk, or soy sauce, are a source of tryptophan. These can be a good option for vegetarians and vegans. Nuts are a good source of protein, healthful fats, and fiber. Snacking on a few nuts between meals can help a person to feel fuller for longer. Healthful, nutrient-dense carbohydrate sources include fruits, vegetables, and whole-grain breads and pastas. The majority of serotonin in the body is made in the gut, while the brain is where a further small amount is made.
Tryptophan needs carbohydrates to be able to reach the brain and create serotonin. A steady supply of energy throughout the day can help to balance mood. Whole grains are digested slowly by the body, which means they release energy gradually. Healthful snacks, such as nuts and seeds or fruit can provide energy between meals. Drinking plenty of fluids during the day keeps the body and brain hydrated.
This is critical for energy levels and correct brain functioning. Having a healthy gut is vital for the production of serotonin. The following can help promote a healthy gut:. There is a link between serotonin and seasonal affective disorder SAD. People can be affected by SAD during the winter months when there is less daylight. It can cause low mood, lack of energy, and disrupted sleep. Sunshine may trigger the production of serotonin.
Exercise has benefits for mental as well as physical health. It may reduce the risk of depression and provide an immediate mood boost as it releases endorphins, which help cope with pain or stress. Feeling positive is often about balance.
Diet, exercise, sleep, and a positive outlook are all key elements to improving mood. Amino acids and proteins. Medical Biochemistry. Philadelphia, PA: Elsevier; chap 2. Updated December Sarika et al 29 found that despite the nutritional superiority of Opaque, a high-tryptophan and high-lysine maize mutant, the physico-biochemical characteristics of its endosperm are not affected.
In an analysis of rice, Wakasa et al 30 found the amount of free tryptophan in a transgenic rice variety was about twice that in seeds in wild-type plants.
The protein-bound tryptophan level was also enhanced. This observation led the authors to suggest that the tryptophan content of rice seeds could be increased transgenetically to improve the nutritional value of the human diet and also animal feeds.
By contrast, Dubouzet et al 31 described a metabolic engineering method used to promote the transformation of tryptophan to serotonin and to serotonin-derived indole compounds in rice calli, suggesting that the method provides a novel approach for the production of tryptophan-derived bioactive compounds. Kita et al 32 discovered that transgenic soybean plants were found to accumulate free tryptophan to levels as high as 3. For analysis, free tryptophan and other amino acids were extracted with sulfosalicylic acid and analyzed by the ninhydrin method using an automated amino acid analyzer.
The high-tryptophan soybeans can be used to increase the tryptophan content of mixed diets. A discussion of reported methods used to analyze the isomeric forms of amino acids simultaneously is beyond the scope of this article. By contributing to food security, a major worldwide challenge, these selected results, and related ongoing studies suggest that the production of novel nutritionally enhanced major food crops via genetic engineering might help meet the worldwide need for inexpensive better-quality foods.
There have been many studies on the utilization of tryptophan from different sources by humans and animals and some of these reports are included here to highlight the potential for tryptophan supplementation fortification. Various studies have investigated the absorption of tryptophan into the human body.
The authors suggest that negative effect of the corn protein zein probably reflects its poor digestibility, resulting in slower absorption of the amino acids from the gut. The effects of dietary tryptophan on the immune system have also been investigated. Tryptophan catabolites can have immunomodulatory functions, such as via the kynurenine pathway.
The dietary role of tryptophan in the immune system has therefore been the subject of study. Brain serotonin, derived from tryptophan, is known to influence affective events, such as mood disorders. They observed significant faster increases and longer-lasting improvement in the ratio with the hydrolyzed tryptophan source versus the intact or pure tryptophan. In a related study, Markus et al 39 found that consumption of a tryptophan-rich egg protein hydrolysate by 17 participants with high and 18 with low chronic stress resulted in an increase in plasma tryptophan uptake into the brain and in improved mood and performance under acute stress exposure, suggesting the therapeutic value of the hydrolysate.
Similarly, Mitchell et al 40 investigated, using a double-blind crossover design, the dose-dependent effects of a tryptophan-rich egg protein hydrolysate on brain tryptophan availability. The results suggest that the hydrolysate is a useful food ingredient that can increase tryptophan availability. The availability of tryptophan in animal feed has also been investigated. These facts should be taken into account in the design of nutritionally improved poultry feed diets supplemented with tryptophan.
Reichl 42 has provided a comprehensive discussion of the kinetics of the absorption and metabolism of amino acids in tissues from the gut into the bloodstream in rodents, cows, pigs, and sheep. The described results indicate that although tryptophan is well absorbed, its absorption is reduced by the presence of other amino acids.
The following observations indicate that tryptophan has been shown to be of paramount importance in infant nutrition. For example, Huang et al 43 discuss the tryptophan requirement of infants in the first month of life. This observation is reinforced by a study with infants breast-fed or fed with a tryptophan-fortified formula.
By contrast, no significant difference was apparent between the breast-fed group and the group fed the tryptophan-fortified formula, suggesting the need for tryptophan fortification to achieve plasma tryptophan levels similar to those in breast-fed infants. These diets are low in protein quality and quantity and in energy.
To overcome these deficiencies, corn can be supplemented either with 2 limiting amino acids tryptophan and lysine or high-quality proteins such as soybean flour. Serna-Saldivar 50 note that the consumption of tortillas flat cakes baked from lime-treated corn without supplementation with high-quality protein foods can lead to the Kwashiorkor disease in infants. This is due to the lack of 2 mentioned essential amino acids. These facts stimulated interest in exploring the nutritional potential of widely consumed corn flour-based tortillas fortified with lysine, tryptophan, and high-quality protein flours.
Here, we briefly mention some of the reported studies,. Tovar and Carpenter 51 found that it appears that the higher protein efficiency ratio, a measure of protein nutritional quality in rats, for corn with added tryptophan as the limiting amino acid as compared with added lysine was due to lower ad libitum food intake with the same weight gain. Amaya-Guerra et al 54 found that soybean fortification of corn tortillas with high-tryptophan soy flour improved brain development of rats, suggesting that the fortification has the potential to enhance the nutrition quality of widely consumed corn tortillas.
The cited studies suggest that fortifications of tortillas with tryptophan or with high-tryptophan soy proteins 55 have the potential to enhance the nutritional quality and health benefits of corn tortillas. It is also worth noting that Delgado et al 56 found that tortillas prepared from high-anthocyanin pigmented maize have lower levels of potentially toxic acrylamide compared with those prepared from nonpigmented corn kernels, suggesting that the phenolic compounds are most likely responsible for the beneficial effect.
Because tryptophan is widely used a dietary supplement for perceived benefits including sleep and mood regulation, there is a need for assessing its safety. This value is generally reinforced by the following experimental observations on the safety of tryptophan in young women and rats. Two studies by Hiratsuka et al 58 , 59 showed that oral administration of tryptophan to 17 healthy Japanese young women at concentrations ranging from 1.
The urinary excretion of nicotinamide and several other metabolites was directly related to consumed tryptophan levels. The authors suggest that because 3-hydroxykinurenine was the most characteristic excreted urinary metabolite, it could serve as a surrogate biomarker for excess intake of tryptophan.
These observations imply that use of tryptophan as a human food or animal feed dietary supplement might not have adverse effects. Shibui et al 44 examined the safety of tryptophan in rats. Feeding an experimental diet with added tryptophan at doses 0 basal diet , 1. However, body weight gain and food consumption significantly decreased in men in the 2. These adverse effects were not observed after a 5-week recovery period, suggesting reversibility of the adverse effects.
The no-observed-adverse-effect level was 1. The authors concluded that tryptophan has a low toxicity profile in rats. Although racemization rates of the 18 different l -amino acid residues in a protein vary, the relative rates in different proteins are similar.
Because the formation d -peptide bonds and cross-linked amino acids such as lanthionine and lysinoalanine can impair digestibility and nutritional quality, there is need to develop a better understanding of these events in order minimize adverse effects on protein nutritional quality and safety. As part of a program to evaluate the chemistry and the nutritional and toxicologic aspects of novel amino acids formed during food processing, including d -amino acids, we compared the weight gain in mice fed with free amino acid diets in which d -tryptophan was substituted for l -tryptophan reviewed by Friedman and Levin 60 , The results indicate that the mice can utilize supplied d -tryptophan in the absence of l -tryptophan; ie, the mice must meet the entire need for l -tryptophan from the d -isomer.
The relative nutritional potency of d -tryptophan compared with l -tryptophan in mice is strongly dose dependent. The maximum growth weight gain of the mice with l -tryptophan was at concentrations of 0.
Thus, the maximum growth of the mice when supplied with d -tryptophan was not achieved until its concentration was 2. Adapted using methods described in Friedman and Gumbmann 62 and Friedman and Levin.
Using mostly methods of supplementing food proteins with free- d -tryptophan, Baker 63 describes variable outcomes for the utilization of d -tryptophan by different animal species.
In humans, the biological utilization of d -tryptophan in the male infant seems to be low, 66 suggesting the need for further exploration of the nutritional utilization in humans of pure d -tryptophan and of d -tryptophan—containing peptides and food proteins.
There is also a need to find out how the biological and nutritional effects of d -tryptophan vary, depending on whether they are consumed in the free state or as part of a peptide or food protein. Based on persuasive evidence, the authors suggest that fertility drops to below replacement levels owing to a high meat diet and that reducing variance in meat consumption might help stabilize the world population growth, a possible major challenge for future generations.
It is noteworthy that we found that the tryptophan content of minced beef is somewhat lower than in several widely consumed plant foods Table 2. Tryptophan has been implicated in a plethora of diseases and conditions because of its fundamental role as a precursor to many bioactive metabolites, leading to its consideration in the improvement of health and nutrition, and as a diagnostic tool. The properties of tryptophan and its involvement in metabolic processes make it a suitable candidate for its investigation as a biomarker for diagnosis, examples of which are provided below.
Cataracts remain a global health issue and their sensitive detection is important. Gakamsky et al 72 found using MS and fluorescence steady-state and lifetime spectroscopy that fluorescence of tryptophan and its derivatives in the postsurgical human and porcine lens samples correlates strongly with cataract grade and age, suggesting that the method can be used to diagnose cataracts at the molecular level.
Using a photo-type multispectral imaging system optimized for the macroscopic imaging of tissues, Baner et al 74 found that tryptophan fluorescence of surgical specimens of colonic neoplasms and normal mucosa after resection could be useful in differentiating normal and cancerous cells because there is an increase in emission intensity from cancerous cells. They also reported that in tissues tryptophan autofluorescence images corrected using green reflectance images might also be useful for displaying neoplasms.
Whether this is generally the case with other proteins merits study. Based on an examination of serum-free amino acid and plasma-free amino acid profiles in samples from healthy controls and 56 patients with clear cell renal cell carcinoma, Lee et al 76 discovered that a combination of serum histidine and plasma tryptophan may be a useful biomarker to detect the renal carcinoma.
A study by Teraishi et al 77 showed that the oral administration of 13C-tryptophan to human volunteers having a major depressive disorder and controls correlated negatively with exhaled maximum 13CO 2 levels, suggesting that the 13C-tryptophan breath test could serve as a novel biomarker for detecting a subgroup of patients with altered increased tryptophan-kynurenine metabolism.
The use of tryptophan to help combat diseases and conditions has also been extensively investigated in a variety of clinical areas. Statistical correlations were observed between tryptophan levels and the severity of symptoms in different groups of patients.
The authors conclude that the tryptophan level is critical and that intake of B vitamins and magnesium with the diet might influence its metabolic homeostasis. Murr et al 79 found in a study with patients with coronary artery disease that low serum tryptophan is associated with immune activation and indicates reduced life expectancy. Mangge et al 80 hypothesize that disturbed tryptophan metabolism breakdown triggered by pro-inflammatory cascades in obese individuals seems to be associated with cardiovascular disease.
This results in an increased serum kynurenine to tryptophan ratios, which can be measured for a better understanding of cardiovascular disease. In addition, the depletion of tryptophan limits protein synthesis, including hemoglobin production that may be associated with a likelihood of fatal cardiovascular events through the reduction in oxygen supply causing anemia.
Because the breakdown of tryptophan is accelerated by exercise, the authors suggest that obese individuals should strive for a balance between food consumption and physical activity. It is worth mentioning that we previously suggested that acrylamide, a reactive molecule that is present in numerous processed plant foods that modifies hemoglobin after consumption, could also adversely affect oxygen transport to tissues.
The authors conclude that an increase in the plasma tryptophan level was significantly associated with a decreased risk of cardiovascular disease and that the Mediterranean diet consisting of extra-virgin olive oil, nuts, fruits, vegetables, and cereals might counteract the deleterious effect of a high kynurenine risk score.
Schulman 83 describes the molecular events that take place during the inhibition of intestinal absorption of a tryptophan derivative by the drug AST that is expected to slow the progression of the chronic kidney disease in humans.
The author mentions a phase 3 trial in progress with about subjects designed to confirm the preliminary data. Because a tryptophan-enriched diet is reported to prevent the age-induced decline of hippocampal serotonin 5-HT production that may contribute to age-related cognitive decline, Musumeci et al 84 further investigated the effect of tryptophan diets on these cellular events and associated multiple biomarkers in rats.
They found that a high tryptophan diet improved passive avoidance impairment of aged rats and partially rescued the age-induced inhibition of transcription factors involved in synaptic plasticity and memory. The authors suggest that the results indicate that enhanced tryptophan intake and the potential increases in 5-HT neurotransmission might help prevent age-related detrimental aspect by inhibiting hippocampal apoptosis.
Because excess tryptophan inhibits the 2 enzymes involved in serotonin synthesis, and increased cerebral levels of neuroactive kynurenine, Badawy 85 hypothesizes that moderate use of tryptophan and decreased anxiety associated with exercise could explain behavioral effects of androgenic anabolic steroids associated with tryptophan metabolism.
In a related study, Badawy 86 discusses the utilization and function of tryptophan in pregnancy. Chen et al 88 assessed the possible association of tryptophan with the development of type 2 diabetes in individuals in China, 51 with diabetes and who remained healthy during a year period.
They determined tryptophan levels using ultra-performance liquid chromatography triple quadrupole MS and found that a the serum tryptophan level was positively and independently associated with the onset risk of diabetes; b patients with higher tryptophan levels had a higher degree of insulin resistance, secretion of triglycerides, and blood pressure; and c the addition of tryptophan seems to enhance the value of existing acid predictors, suggesting that tryptophan might represent a new biomarker associated with diabetes risk, but this awaits validation in other and larger populations.
In the consideration of diabetes, it is also worth mentioning that Imahori et al 89 isolated 2 known compounds 4-quinlylaldoxime and indolealdehyde and 2 novel compounds formed during the in vitro reaction of tryptophan and glucose at physiological temperature and pH.
One of the novel compounds, indolealdehyde, was mutagenic in the Salmonella Typhimurium assay. Although 4-quinlylaldoxime was detected in rat diabetes extracts, the isolated new compounds were not detected in rat plasma. The authors suggest that genotoxic amino-carbonyl reaction products may be formed under diabetic conditions that can induce genetic damage to tissues. Strasser et al 90 discuss the bioanalytical procedures for the determination of the concentrations of tryptophan and phenylalanine and their respective first stable intermediates kynurenine and tyrosine.
The authors suggest that these immunometabolic parameters, along with other biomarkers, should be monitored in studies of the mechanisms of progression of inflammation-associated with depression and potential therapy. Nikolaus et al 92 reported that the serum levels of tryptophan were significantly lower in patients with inflammatory bowel disease IBD than in controls, with a stronger reduction in levels in patients with Crohn disease.
These observations and a detailed examination of associated biomarkers and metabolites, especially quinolinic acid, show a high activity of tryptophan degradation in patients with IBD, suggesting that tryptophan deficiency could contribute to the development or aggravation of the disease. Administration of high doses of metabolites nicotinamide, indolealdehyde might modify the microbiome and shunt tryptophan metabolism toward anti-inflammatory pathways.
Because the oxidation of tryptophan owing to immune induction of the enzyme indoleamine 2,3 dioxygenase is considered the main cause of tryptophan depletion in patients with HIV, Bipath et al 93 examined plasma tryptophan levels in low-income sub-Saharan HIV-infected patients and 60 HIV-negative controls.
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