Activation of Liver Tryptophan Pyrrolase Mediates the Decrease in Tryptophan Availability to the Brain after Acute Alcohol Consumption by Normal Subjects

Badawy, Abdulla A.-B.; Doughrty, Donald M.; Marsh-Richard, Dawn M.; Steptoe, Alex

doi:10.1093/alcalc/agp005

Cited by 35 publications

(24 citation statements)

References 22 publications

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“…Acute alcohol intake activates TDO, while chronic alcohol use inhibits TDO activity. During withdrawal from heavy alcohol use, TDO activity is again increased (Badawy, 2002, Badawy et al, 2009, Branchey et al, 1984b). Our data indicates that both tryptophan and kynurenine concentrations may increase after a month of abstinence, possibly because of increased dietary support and improved intestinal absorption during recovery.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, serotonin (5-HT) bioavailability, widely believed to be key in the pathogenesis of depressive disorders (Coppen, 1967, Maes and Meltzer, 1995), is amenable to alcohol consumption (LeMarquand et al, 1994). Indeed, both acute and chronic alcohol intake have a profound effect on the metabolism of tryptophan, which is the essential amino acid precursor for 5-HT synthesis (Badawy, 2002, Badawy et al, 2009). These intersecting pathways underscore the need to include alcohol measures when studying the mechanisms of depression, and the need to examine the biological processes of depression among people with AUD.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, alcohol-induced liver damage can result in altered TDO activity, leading to a disturbance in tryptophan metabolism and altered levels of circulating tryptophan and kynurenine. In the context of alcohol misuse, factors such as duration of and time since alcohol intake have been shown to determine the nature of tryptophan dysregulation (Badawy et al, 2009, Friedman et al, 1988). …”

Section: Introductionmentioning

confidence: 99%

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The Relationship of Alcohol Use Disorders and Depressive Symptoms to Tryptophan Metabolism: Cross-Sectional Data from a Nepalese Alcohol Treatment Sample

Lien

Martínez

Hestad

et al. 2015

Alcohol Clin Exp Res

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Background Activation of the kynurenine pathway of tryptophan metabolism results in increased production of potentially depressogenic tryptophan catabolites and a reduction in tryptophan availability for serotonin synthesis. Since alcohol consumption affects tryptophan metabolism and disposition, we determined serum levels of kynurenine, tryptophan and the kynurenine/tryptophan ratio (KT ratio) in alcohol-use disorder (AUD) patients and compared their levels considering abstinence duration, AUD severity and comorbid depression. Methods The study sample included 169 AUD inpatients from eight alcohol treatment facilities in Kathmandu, Nepal. The Composite International Diagnostic Interview was administered to generate the AUD diagnosis. The Alcohol Use Disorder Identification Test (AUDIT) captured AUD severity and patterns of alcohol use. The Hopkins Symptom Checklist-25 was used to reveal current depressive symptoms. Serum kynurenine and tryptophan levels were determined by high-performance liquid chromatography and tryptophan degradation was measured by KT ratio (kynurenine/tryptophan × 103). Results Patients with above average AUDIT scores had higher mean serum levels of kynurenine (2.1μM±0.7 vs 1.8 μM ±0.6, p= 0.006) and KT ratios (48.6±17.6 vs 40.4±14.3, p=0.002) than those with below average scores. Patients with current depressive symptoms had higher mean tryptophan concentrations (49.9 μM ±13 vs 45.7 μM±14.1, p= 0.047) and lower KT ratios (41.4 μM ±14 vs 47.5 μM ±17.6, p=0.028) compared to patients whose reported depressive symptoms were below the standard cut-off. Higher tryptophan levels and lower KT ratios in the depressed group was specific to patients with longer abstinence and higher AUD severity. Conclusions Depression-related deregulation in tryptophan metabolism was found to depend on length of abstinence and on AUD severity. Together, results suggest that in AUD populations, peripheral tryptophan metabolism is subject to interactions between AUD severity and depressive symptoms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Relationship of Alcohol Use Disorders and Depressive Symptoms to Tryptophan Metabolism: Cross-Sectional Data from a Nepalese Alcohol Treatment Sample

Lien

Martínez

Hestad

et al. 2015

Alcohol Clin Exp Res

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“…Glucocorticoids thus produced cause tryptophan degradation by activating hepatic degradation of tryptophan 2,3-dioxygenase (TDO), which, along with cytokine-induced IDO in the brain, once again produces metabolites biased toward the neurotoxic edge (97, 98). TDO enzyme is activated upon acute alcohol consumption, subsequently inhibited with chronic alcohol drinking, and again surges during ethanol withdrawal (99–101). The altered tryptophan metabolism reportedly lasts for several months into abstention, as shown in a comparative study of 4 and 11 weeks of abstinence, wherein longer abstinence was related to increased kynurenine levels (102, 103).…”

Section: Neuroimmune Dysregulation In Aud–depression Comorbiditymentioning

confidence: 99%

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression

Neupane

2016

Front. Immunol.

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Bidirectional communication links operate between the brain and the body. Afferent immune-to-brain signals are capable of inducing changes in mood and behavior. Chronic heavy alcohol drinking, typical of alcohol use disorder (AUD), is one such factor that provokes an immune response in the periphery that, by means of circulatory cytokines and other neuroimmune mediators, ultimately causes alterations in the brain function. Alcohol can also directly impact the immune functions of microglia, the resident immune cells of the central nervous system (CNS). Several lines of research have established the contribution of specific inflammatory mediators in the development and progression of depressive illness. Much of the available evidence in this field stems from cross-sectional data on the immune interactions between isolated AUD and major depression (MD). Given their heterogeneity as disease entities with overlapping symptoms and shared neuroimmune correlates, it is no surprise that systemic and CNS inflammation could be a critical determinant of the frequent comorbidity between AUD and MD. This review presents a summary and analysis of the extant literature on neuroimmune interface in the AUD–MD comorbidity.

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“…Since plasma cortisol mirrored these findings, it is likely that glucocorticoids were responsible for the induction of hepatic TDO. More recently, it has been established in humans that even a short, 2 h exposure to alcohol causes a significant reduction in plasma tryptophan and leads to an increase in kynurenine (Badawy et al, 2009). Data such as these in control human subjects establish that short term alcohol intoxication drives tryptophan metabolism toward the kynurenine pathway.…”

Section: Does Indoleamine 23-dioxygenase Mediate Alcohol-associated mentioning

confidence: 99%

Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders

Kelley

Dantzer

2011

Brain, Behavior, and Immunity

127

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Alcohol abuse changes behavior and can induce major mood disorders such as depression. Recent evidence in pre-clinical rodent models and humans now supports the conclusion that the innate immune system is an important physiological link between alcoholism and major depressive disorders. Deficiency of toll-like receptor 4 (TLR4), a protein that has been known to immunologists for 50 years, not only prevents lipopolysaccaride (LPS)-induced sickness behavior but recently has been demonstrated to induce resistance to chronic alcohol ingestion. Activation of the immune system by acute administration of LPS, a TLR4 agonist, as well as chronic infection with Bacille Calmette-Guérin, (BCG) causes development of depressive-like behaviors in pre-clinical rodent models. Induction of an enzyme expressed primarily in macrophages and microglia, 2,3 indoleamine dioxygenase, shunts tryptophan catabolism to form kynurenine metabolites. This enzyme is both necessary and sufficient for expression of inflammation-induced depressive-like behaviors in mice. New findings have extended these concepts to humans by showing that tryptophan catabolites of 2,3 indoleamine dioxygenase are elevated in the cerebrospinal fluid of cancer patients treated with the recombinant cytokine interferon-α. The remarkable conservation from mice to humans of the impact of inflammation on mood emphasizes the ever-expanding role for cross-talk among diverse physiological symptoms that are likely to be involved in the pathogenesis of alcohol abuse. These findings present new and challenging opportunities for scientists who are engaged in brain, behavior and immunity research.

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Activation of Liver Tryptophan Pyrrolase Mediates the Decrease in Tryptophan Availability to the Brain after Acute Alcohol Consumption by Normal Subjects

Abstract: We conclude that activation of liver Trp pyrrolase mediates the depletion of plasma Trp and the decrease in its availability to the brain induced by acute ethanol consumption.

Cited by 35 publications

References 22 publications

The Relationship of Alcohol Use Disorders and Depressive Symptoms to Tryptophan Metabolism: Cross-Sectional Data from a Nepalese Alcohol Treatment Sample

The Relationship of Alcohol Use Disorders and Depressive Symptoms to Tryptophan Metabolism: Cross-Sectional Data from a Nepalese Alcohol Treatment Sample

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression

Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders

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