TY - JOUR
T1 - Tyrosine metabolism during interferon-alpha administration
T2 - Association with fatigue and CSF dopamine concentrations
AU - Felger, Jennifer C.
AU - Li, Li
AU - Marvar, Paul J.
AU - Woolwine, Bobbi J.
AU - Harrison, David G.
AU - Raison, Charles L.
AU - Miller, Andrew H.
N1 - Funding Information:
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. 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.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Depression
KW - Dopamine synthesis
KW - Fatigue
KW - Interferon-alpha
KW - Tetrahydrobiopterin
KW - Tyrosine metabolism
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U2 - 10.1016/j.bbi.2012.10.010
DO - 10.1016/j.bbi.2012.10.010
M3 - Article
C2 - 23072726
AN - SCOPUS:84878160653
SN - 0889-1591
VL - 31
SP - 153
EP - 160
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -