Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations
Open accessAbstract
Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n=25) compared to controls (n=9), and were negatively correlated with CSF DA (r=-0.59, df=15, p<0.05) and its metabolite, homovanillic acid (r=-0.67, df=15, p<0.01), and positively correlated with fatigue (r=0.44, df=23, p<.05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n=12) compared to controls (n=7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r=-0.57, df=12, p<0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response.
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In IFNα-treated patients, CSF BH4 concentrations are negatively correlated with CSF IL-6 levels.
“Indeed, CSF concentrations of BH4 have been shown to be negatively correlated with CSF levels of IL-6 in patients treated with the inflammatory cytokine IFNα74.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [74]
The Results section reports a significant negative correlation between CSF BH4 and CSF IL-6 (r=−0.57, p<0.05). However, it reports this correlation for all patients in the analysis, which included controls, rather than specifically for IFNα-treated patients. (LLM, conf=0.88)
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- Authors
- Felger, J. C., Li, L., Marvar, P. J., Woolwine, B. J., Harrison, D. G., Raison, C. L., & Miller, A. H.
- Affiliations
- Emory University (US)
- Vanderbilt University (US)
- University of Arizona (US)
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 31
- Pages
- 153-160
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3578984
- OpenAlex
- W2031215299
- Cited by
- 176
- References
- 79
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 11 · 2023: 15 · 2022: 16 · 2021: 12 · 2020: 14 · 2019: 15 · 2018: 16 · 2017: 10 · 2016: 15 · 2015: 13 · 2014: 11 · 2013: 13 · 2012: 1
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health to CLR (K23 MH064619, R01 MH070553)
- JF (F32 MH093054)
- AHM (K05 MH069124, R01 HL073921, MHR01MH075102, T32 MH020018)
- Emory Center for AIDS Research (P30 AI050409)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- interferon-alpha, tyrosine metabolism, phenylalanine hydroxylase, dopamine, homovanillic acid, fatigue, tetrahydrobiopterin, dihydrobiopterin, interleukin-6, hepatitis C, ribavirin, neuroinflammation
- MeSH terms
- Adult, Antiviral Agents, Dopamine, Fatigue, Female, Hepatitis C, Humans, Longitudinal Studies, Male, Middle Aged, Phenylalanine, Tyrosine, Interleukin-6, Interferon-alpha
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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