RESUMO
OBJECTIVE: To determine whether additional supplementation of tryptophan (Trp) and tyrosine (Tyr) improve serotonin and dopamine metabolism in individuals with phenylketonuria treated with large neutral amino acid (LNAA) tablets. STUDY DESIGN: Ten adult individuals with phenylketonuria participated in a randomized, double-blind, placebo-controlled cross-over study consisting of three 3-week phases: washout, treatment with LNAA tablets plus supplementation with either Trp and Tyr tablets or placebo, and LNAA tablets plus the alternate supplementation. An overnight protocol to measure blood melatonin, a serotonin metabolite in the pinealocytes, and urine 6-sulfatoxymelatonin and dopamine in first-void urine specimens was conducted after each phase. RESULTS: Serum melatonin and urine 6-sulfatoxymelatonin and dopamine levels were increased in the LNAA phase (LNAA plus placebo) compared with the washout phase. Serum melatonin and urine 6-sulfatoxymelatonin were not increased in the active phase (LNAA plus Trp + Tyr) compared with the LNAA phase, although plasma Trp:LNAA was increased compared with the LNAA phase. Among 7 subjects with a plasma Trp/LNAA >0.03, a negative correlation between urine 6-sulfatoxymelatonin and plasma phenylalanine levels was observed (r = -0.072). Urine dopamine levels and plasma Tyr:LNAA were increased in the active phase compared with the LNAA phase. CONCLUSION: Melatonin levels were not increased with the higher dose of Trp supplementation, but dopamine levels were increased with the higher dose of Tyr supplementation. Serotonin synthesis appears to be suppressed by high phenylalanine levels at the Trp hydroxylase level.
Assuntos
Aminoácidos Neutros/uso terapêutico , Biomarcadores/sangue , Dopamina/sangue , Melatonina/análogos & derivados , Melatonina/sangue , Fenilcetonúrias/tratamento farmacológico , Triptofano/uso terapêutico , Tirosina/uso terapêutico , Adulto , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Masculino , Melatonina/urina , Pessoa de Meia-Idade , Fenilcetonúrias/sangue , Fenilcetonúrias/urina , Serotonina/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To determine whether levels of melatonin in blood and urine can serve as a peripheral biomarker to reflect brain serotonin synthesis in individuals with phenylketonuria (PKU). STUDY DESIGN: We measured the levels of melatonin, a serotonin metabolite in the pinealocytes, in the blood and urine of individuals with PKU in a randomized double-blind placebo controlled crossover study consisting of three 3-week phases in 10 adults with PKU: phase 1 (washout), phase 2 (supplementation of large neutral amino acid [LNAA] tablets or placebo), and phase 3 (alternate supplementation). An overnight protocol to measure blood melatonin and urine 6-sulfatoxymelatonin and dopamine in first void urine specimens was conducted after each phase for subjects with PKU and once in 10 controls. RESULTS: Significantly lower concentrations of these neurotransmitter metabolites were observed in subjects with PKU after phase 1 compared with controls (serum melatonin P = .008, urine melatonin P = .0043, urine dopamine P < .0001), with significant increases after LNAA supplementation compared with the placebo phase (serum melatonin P = .0008, urine melatonin P = .0008, urine dopamine P = .0005). The mean tryptophan/LNAA and tyrosine/LNAA ratios were markedly lower in subjects with PKU compared with controls, and these ratios were significantly increased in the LNAA phase compared with the placebo phase (P = .016, P = .0003, respectively). Blood phenylalanine levels in subjects with PKU were not significantly different between placebo and LNAA phases (P = .74). CONCLUSION: Blood and urine melatonin levels may serve as biomarkers reflecting brain serotonin synthesis in subjects with PKU. Because this cannot be evaluated using blood phenylalanine levels, it may provide information on neurotransmitter metabolism for optimal dietary management.