Tryptophan
Parallel to
neopterin formation, cytokine interferon-g also induces
degradation of tryptophan. In various diseases increased neopterin
concentrations correlate with decrease of tryptophan and increase of
tryptophan catabolites.
Interferon-gamma-induced
conversion of tryptophan: immunologic and neuropsychiatric aspects
Wirleitner B, et al. Institute of Medical Chemistry and Biochemistry,
University of Innsbruck, Innsbruck, Austria
(Curr Med Chem 2003; 10: 1581-91)
Tryptophan is an essential amino acid and the least abundant constituent of
proteins. In parallel it represents a source for two important biochemical
pathways: the generation of neurotransmitter 5-hydroxytryptamine
(serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase,
and the formation of kynurenine derivatives and nicotinamide adenine
dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan
2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is
located in the liver cells, IDO is expressed in a large variety of cells
and is inducible by the cytokine interferon-gamma. Therefore, accelerated
tryptophan degradation is observed in diseases and disorders concomitant
with cellular immune activation, e. g. infectious, autoimmune, and
malignant diseases, as well as during pregnancy. According to the
cytostatic and antiproliferative properties of tryptophan-depletion on T
lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate
immune response via degradation of tryptophan. Especially in states of
persistent immune activation availability of free serum tryptophan is
diminished and as a consequence of reduced serotonin production,
serotonergic functions may as well be affected. Accumulation of neuroactive
kynurenine metabolites such as quinolinic acid may contribute to the
development of neurologic/psychiatric disorders. Thus, IDO seems to
represent a link between the immunological network and neuroendocrine
functions with far reaching consequences in regard to the psychological
status of patients. These observations provide a basis for the better
understanding of mood disorder and related symptoms in chronic diseases.
Immune
reaction links disease progression in cancer patients with depression
Murr C, et al. Institute for Medical Chemistry and Biochemistry,
Innsbruck, Austria
(Med Hypotheses 2000; 55: 137-40)
Mood disturbances and depression are supposed to have a negative impact on
patients' outcome in malignant tumour disease. On the other hand, poor
prognosis in cancer patients is associated with chronic immune challenge
which is paralleled by enhanced degradation of the essential amino acid
tryptophan and thus decreased plasma tryptophan concentrations. Because
tryptophan is precursor for the biosynthesis of the neurotransmitter
serotonin (= 5-hydroxytryptamine, 5HT), low tryptophan concentrations will
lead to decreased availability of serotonin which finally increases the
susceptibility for the development of mood disturbances and depression in
the patients. Thus, the development of depression in cancer patients may
result from chronic cellular immune stimulation. In conclusion, a more
aggressive tumour rather than depression will be responsible for worse
outcome of cancer patients and will be associated with a more drastic
challenge of the immune system, as a side effect leading to
neurotransmitter disturbances.
Serum
tryptophan decrease correlates with immune activation and impaired quality
of life in colorectal cancer
Huang A, et al. Department of Surgery, Faculty of Medicine, Imperial
College of Science, Technology and Medicine, Chelsea and Westminster
Hospital, 369 Fulham Road, London SW10 9NH, UK
(Br J Cancer 2002; 86: 1691-6)
Cancer-related indoleamine (2,3)-dioxygenase up-regulation by
interferon-gamma might influence quality of life by depleting serum
tryptophan. We correlated serum tryptophan levels with immune activation
and quality of life in patients with colorectal liver metastases. Venous
blood was sampled from patients with primary colorectal cancer and from
patients with metachronous colorectal liver metastases who completed
quality of life and psychological questionnaires. Serum tryptophan,
kynurenine, neopterin, interleukin 2 soluble receptor alpha (IL-2 sRalpha),
soluble tumour necrosis factor receptor I (sTNF RI), interleukin 6, and
C-reactive protein were measured. Liver metastasis volume was estimated by
computerised tomography, and survival from blood sampling was noted.
Sixty-six patients with colorectal cancer were studied (39 males; median
age 66 years) of whom 25 had colorectal liver metastases only (17 males;
median age 62 years; median liver metastasis volume 208 ml; median survival
234 days). Reduced serum tryptophan was significantly associated with
Rotterdam Symptom Checklist physical symptom (r=-0.51, P=0.01) and Sickness
Impact Profile (r=-0.42, P=0.04) scores, and correlated with increased
serum neopterin (r=-0.36, P=0.003), IL-2 sRalpha (r=-0.51, P=0.01) and sTNF
RI (r=-0.45, P=0.02) levels. Stepwise regression analyses suggested that
serum tryptophan was an independent predictor of Rotterdam Symptom
Checklist physical symptom (regression coefficient -20.78, P=0.01) and
Sickness Impact Profile (regression coefficient -109.09, P=0.04) scores.
The results supported a role for interferon-gamma-mediated serum tryptophan
decrease in cancer-induced quality of life deterioration. Copyright 2002
Cancer Research UK
Interferon-alpha-induced changes
in tryptophan metabolism. relationship to depression and paroxetine
treatment
Capuron L, et al. Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia 30322, USA
(Biol Psychiatry 2003; 54: 906-14)
Tryptophan (TRP) degradation
into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during
immune activation may contribute to development of depressive symptoms
during interferon (IFN)-alpha therapy.: Twenty-six patients with malignant
melanoma were randomly assigned in double-blind fashion to receive either
placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment and
continuing for the first 12 weeks of IFN-alpha therapy. At treatment
initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements
of TRP, KYN, and neopterin (a marker of immune activation), were obtained,
along with structured assessments of depression, anxiety, and
neurotoxicity. Regardless of antidepressant treatment status, all patients
exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio
during IFN-alpha therapy. Among antidepressant-free patients, patients who
developed major depression exhibited significantly greater increases in KYN
and neopterin concentrations and more prolonged decreases in TRP
concentrations than did nondepressed, antidepressant-free patients.
Moreover, in antidepressant-free patients, decreases in TRP correlated with
depressive, anxious, and cognitive symptoms, but not neurovegetative or
somatic symptoms. No correlations were found between clinical and
biological variables in antidepressant-treated patients. The results
suggest that reduced TRP availability plays a role in IFN-alpha-induced
depressive symptoms, and paroxetine, although not altering the KYN or
neopterin response to IFN-alpha, attenuates the behavioral consequences of
IFN-alpha-mediated TRP depletion.