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Author Notes:

Corresponding author. Address: Winship Cancer Institute, Emory, University School of Medicine, 1365-B Clifton Road, 5th Floor, Atlanta, GA 30322, USA. jfelger@gmail.com

The authors would also like to thank Keith W. Kelley, Robert Dantzer, and MA Lawson for HPLC analysis of dopamine and metabolites, and Jon Lowe at ARUP Laboratories (Salt Lake City, Utah) for the analysis of phenylalanine and tyrosine concentrations.

Conflict of Interest Statement: All authors declare that there are no conflicts of interest, and all financial disclosures are listed for each author: Charles L. Raison serves as a consultant for Pamlab LLC and Biolex Therapeutics; Andrew H. Miller has served as a consultant for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Lundbeck Research USA, F. Hoffmann-La Roche Ltd., Schering-Plough Research Institute and Wyeth/Pfizer Inc. and has received research support from Centocor Inc., GlaxoSmithKline, and Schering-Plough Research Institute; Jennifer C. Felger, Li Li, Paul J. Marvar, Bobbi J. Woolwine, and David G. Harrison have nothing to declare.

Subjects:

Research Funding:

This study was supported in part by grants from the National Institutes of Health to CLR (K23 MH064619, R01 MH070553), JF (F32 MH093054), and AHM (K05 MH069124, R01 HL073921, MHR01MH075102, T32 MH020018) as well as the Emory Center for AIDS Research (P30 AI050409).

In addition, the study was supported by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program and PHS Grant M01 RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Neurosciences
  • Neurosciences & Neurology
  • Interferon-alpha
  • Dopamine synthesis
  • Tyrosine metabolism
  • Tetrahydrobiopterin
  • Depression
  • Fatigue
  • MAJOR DEPRESSIVE DISORDER
  • PLASMA TETRAHYDROBIOPTERIN LEVELS
  • DOUBLE-BLIND TRIAL
  • QUINOLINIC ACID
  • IMMUNE ACTIVATION
  • RESIDUAL SYMPTOMS
  • CANCER-PATIENTS
  • SERUM FOLATE
  • NITRIC-OXIDE
  • RISK-FACTOR

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Tools:

Journal Title:

Brain, Behavior, and Immunity

Volume:

Volume 31

Publisher:

, Pages 153-160

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

Copyright information:

© 2012 Elsevier Inc..

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