Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.
Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.
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DOI：
10.1016/j.bbi.2012.10.010
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发表时间：
2013-07
影响因子：
15.1
通讯作者：
Miller, Andrew H.
中科院分区：
文献类型：
--
作者：
Felger, Jennifer C.;Li, Li;Marvar, Paul J.;Woolwine, Bobbi J.;Harrison, David G.;Raison, Charles L.;Miller, Andrew H.
长期暴露于干扰素（IFN）-α，一种先天免疫细胞因子，产生高比率的行为障碍，包括抑郁和疲劳。这些作用可能通过IFN-α对基底神经节中多巴胺（DA）代谢的作用来介导。苯丙氨酸（Phen）转化为酪氨酸（Tyr）（DA的主要氨基酸前体）的减少与炎症有关，可能反映了苯丙氨酸羟化酶（PAH）活性的降低。本研究调查了外周Phen/Tyr比值与脑脊液（CSF）中DA及其代谢产物浓度的关系，受试者接受IFN-α加利巴韦林治疗丙型肝炎，对照组等待IFN-α治疗。与对照组（n=9）相比，IFN-α治疗组（n=25）的血浆Phen/Tyr比值显著升高，并与CSF DA呈负相关（r=-0.59，df=15，p<0.05）及其代谢产物高香草酸（r=-0.67，df=15，p<0.01），并与疲劳呈正相关（r=0.44，df=23，p<0.05），在IFN-α治疗的患者中，而不是对照组。鉴于四氢生物蝶呤（BH 4）在Phen转化为Tyr的PAH中的作用，在一个患者亚组中检查了BH 4及其无活性氧化形式二氢生物蝶呤（BH 2）的CSF浓度沿着CSF白细胞介素（IL）-6。与对照组（n=7）相比，IFN-α治疗患者（n=12）的BH 2浓度显着增加，并且CSF BH 4浓度降低与CSF IL-6升高相关（r=-0.57，df=12，p<0.05）。这些结果表明，IFN-α与Phen向Tyr的外周转化减少有关，而外周转化减少又与脑中DA减少以及疲劳有关。这些改变可能与继发于IFN-α诱导的CNS炎症反应激活的BH 4氧化有关。
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<0.05) 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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影响因子：
15.1
作者：
Felger, Jennifer C.;Alagbe, Oyetunde;Pace, Thaddeus W. W.;Woolwine, Bobbi J.;Hu, Fang;Raison, Charles L.;Miller, Andrew H.
通讯作者：
Miller, Andrew H.
影响因子：
6.9
作者：
Felger, J. C.;Cole, S. W.;Pace, T. W. W.;Hu, F.;Woolwine, B. J.;Doho, G. H.;Raison, C. L.;Miller, A. H.
通讯作者：
Miller, A. H.
DOI：
10.1016/j.ijrobp.2007.05.076
发表时间：
2007-12-01
影响因子：
7
作者：
Butler, Jerome M., Jr.;Case, L. Douglas;Shaw, Edward G.
通讯作者：
Shaw, Edward G.
影响因子：
10.6
作者：
Capuron, Lucile;Schroecksnadel, Sebastian;Fuchs, Dietmar
通讯作者：
Fuchs, Dietmar
影响因子：
--
作者：
Capuron L;Pagnoni G;Drake DF;Woolwine BJ;Spivey JR;Crowe RJ;Votaw JR;Goodman MM;Miller AH
通讯作者：
Miller AH