Immune activation and inflammation increase the plasma phenylalanine-to-tyrosine ratio

The proinflammatory cytokine interferon (IFN) γ activates GTP-cyclohydrolase I. In turn, the production of neopterin in human monocytic cells and of 5,6,7,8-tetrahydrobiopterin (BH4) in other human cells and cells of other species is markedly upregulated. BH4 is cofactor for the biosynthesis of the neurotransmitters 5-hydroxytryptamine (serotonin) and the catecholamines dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). The finding of increased neopterin concentrations in patients with viral infections, autoimmune syndromes, malignant tumors, and during treatment with specific cytokines corresponds well with its immunobiological background. However, there is no clear information about BH4 concentrations in these patients. Furthermore, higher blood phenylalanine (Phe)-to-tyrosine (Tyr) ratios have been described in patients with ovarian cancer, after multiple trauma and with sepsis, in patients with HIV-1 infection, in elderly individuals, and in patients with HCV infection under IFN-α therapy. Recent studies already showed that the alterations of Phe metabolism are associated with mood changes and depression. Results point to an impaired hydroxylation of Phe when the enzyme phenylalanine 4-hydroxylase (PAH) is less efficient. As the decrease of PAH activity might result from a diminished availability of BH4, the determination of the Phe/Tyr ratio may serve as an indirect measure of BH4 availability.