Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.
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.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA. jfelger@gmail.com
Jennifer C
JC
Felger
Li
L
Li
Paul J
PJ
Marvar
Bobbi J
BJ
Woolwine
David G
DG
Harrison
Charles L
CL
Raison
Andrew H
AH
Miller
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004298:Dopamine / Q000134:cerebrospinal fluid*; D005221:Fatigue / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010649:Phenylalanine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D000998:Antiviral Agents; D016898:Interferon-alpha; D015850:Interleukin-6; D014443:Tyrosine; D010649:Phenylalanine; D004298:Dopamine