Background: One of the major metabolic consequences of using nitisinone to treat patients with alkaptonuria is that circulating tyrosine concentrations increase. As tyrosine is required for the biosynthesis of catecholamine neurotransmitters, it is possible that their metabolism is altered as a consequence. Herein we report the 24-h urinary excretion of normetadrenaline (NMA), metadrenaline (MA), 3-methoxytyramine (3-MT) (catecholamine metabolites) and 5-hydroxyindole acetic acid (5-HIAA, metabolite of serotonin) in a cohort of AKU patients before and after a 4-week treatment trial with nitisinone.
Materials and Methods: 24 h urinary excretions of NMA, MA, 3-MT and 5-HIAA were determined by liquid chromatography tandem mass spectrometry. Interassay coefficient of variation was <10% for all analytes measured, at all concentrations tested.
Results: Urine samples were assayed at baseline (pre-nitisinone, n = 36) and 4 weeks later; 7 received no nitisinone (4 male, mean age (±SD) 46.3 (16.4) years), and 29 received a daily dose of nitisinone [1 mg (n = 7, 6 male, mean age 45.9 (10.9) years), 2 mg (n = 8, 5 male, mean age 43.9 (13.7) years), 4 mg (n = 8, 5 male, mean age 47.3 (10.7) years) and 8 mg (n = 6, 4 male, mean age 53.8 (8.3) years)]. 3-MT concentrations increase significantly (p < 0.01, at all doses) following nitisinone therapy but not in a dose-dependent manner. NMA concentrations decreased (p < 0.05, at all doses) following nitisinone therapy at all doses. 5-HIAA concentrations decreased following nitisinone therapy and were significantly lower at a daily dose of 8 mg only (p < 0.05).
Conclusions: This study shows that catecholamine and serotonin metabolism is altered by treatment with nitisinone.
This is a preview of subscription content, log in to check access.
Banks A, Dutton JJ, Phillipson K et al (2014) Development of a LC-MS/MS method for the measurement of total fractionated urine metadrenalines and determination of a healthy population reference range. Clin Chem Lab Med 52(11):eA307Google Scholar
Bendadi F, de Koning TJ, Visser G et al (2014) Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone. J Pediatr 164:398–401CrossRefGoogle Scholar
Davison AS, Milan AM, Hughes AT et al (2015) Serum concentrations and urinary excretion of tyrosine and homogentisic acid in normal subjects. Clin Chem Lab Med 53:e81–e83CrossRefGoogle Scholar
de Jong WHA, Eisenhofer G, Post WJ et al (2009) Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab 94:2841–2849CrossRefGoogle Scholar
De Laet C, Munoz VT, Jaeken J, FranÅois B et al (2011) Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1. Dev Med Child Neurol 53:962–964CrossRefGoogle Scholar
Eisenhofer G, McCarty R, Pacak K et al (1996) Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat. Naunyn Schmiedeberg's Arch Pharmacol 354:287–294CrossRefGoogle Scholar
Eisenhofer G, Kopin IJU, Goldstein DS (2004) Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 56:331–349CrossRefGoogle Scholar
Elenkov IJ, Wilder RL, Chrousos GP et al (2000) The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638PubMedGoogle Scholar
Graefe KH, Friedgen B, Wolfel R et al (1997) 1,1-Diisopropyl-2,4-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines. Naunyn Schmiedeberg's Arch Pharmacol 356:115–125CrossRefGoogle Scholar
Grossman F, Potter WZ (2009) Catecholamines in depression: a cumulative study of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed patients versus healthy volunteers at the NIMH. Psychiatry Res 87:21–27CrossRefGoogle Scholar
Harding CO, Winn SR, Gibson KM et al (2014) Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU). J Inherit Metab Dis 37(5):735–743CrossRefGoogle Scholar
Hillgartner MA, Coker SB, Koenig AE et al (2016) Tyrosinemia type I and not treatment with NTBC causes slower learning and altered behavior in mice. J Inherit Metab Dis 39:673–682CrossRefGoogle Scholar
Hughes JW, Watkins L, Blumenthal JA et al (2004) Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res 57:353–358CrossRefGoogle Scholar
Hughes AT, Milan AM, Davison AS et al (2015) Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry. Ann Clin Biochem 52(5):597–605CrossRefGoogle Scholar
Introne WJ, Perry MB, Troendle J et al (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103:307–314CrossRefGoogle Scholar
Lindstedt S, Holme E, Lock EA et al (1992) Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340(8823):813–817CrossRefGoogle Scholar
Lynn-Bullock CP, Welshhans K, Pallas SL et al (2004) The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J Chem Neuroanat 27:129–138CrossRefGoogle Scholar
Masurel-Paulet A, Poggi-Bach J, Rolland MO et al (2008) NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis 31:81–87CrossRefGoogle Scholar
McKiernan PJ (2013) Nitisinone for the treatment of hereditary tyrosinemia type I. Expert Opin Orphan Drugs 1:491–497CrossRefGoogle Scholar
McKiernan PJ, Preece MA, Chakrapani A (2015) Outcome of children with hereditary tyrosinaemia following newborn screening. Arch Dis Child 100:738–741CrossRefGoogle Scholar
Milan AM, Hughes AT, Davison AS et al (2017) The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool. Ann Clin Biochem 54:323–330CrossRefGoogle Scholar
Milch RA (1960) Studies of alcaptonuria: inheritance of 47 cases in eight highly inter-related Dominican kindreds. Am J Hum Genet 12:76–85PubMedPubMedCentralGoogle Scholar
Olsson B, Cox TF, Psarelli EE et al (2015) Relationship between serum concentrations of nitisinone and its effect on homogentisic acid and tyrosine in patients with alkaptonuria. J Inherit Metab Dis Rep 24:21–27Google Scholar
Phomphutkul C, Introne WJ, Perry MB et al (2002) Natural history of alkaptonuria. N Engl J Med 347:2111–2121CrossRefGoogle Scholar
Pratt O (1982) Transport inhibition in the pathology of phenylketonuria and other inherited metabolic diseases. J Inherit Metab Dis 5:S75–S81CrossRefGoogle Scholar
Ranganath LR, Jarvis JC, Gallagher JA (2013) Recent advances in management of alkaptonuria. J Clin Pathol 66:367–373CrossRefGoogle Scholar
Ranganath LR, Milan AM, Hughes AT et al (2016) Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis 75(2):362–367CrossRefGoogle Scholar
Roy A, Linnoila M, Karoum F et al (1986a) Relative activity of metabolic pathways for norepinephrine in endogenous depression. Acta Psychiatr Scand 73:624–628CrossRefGoogle Scholar
Roy A, Pickar D, Douillet P et al (1986b) Urinary monoamines and monoamine metabolites in subtypes of unipolar depressive disorder and normal controls. Psychol Med 16:541–546CrossRefGoogle Scholar
Suwannarat P, O’Brien K, Perry MB et al (2005) Use of nitisinone in patients with alkaptonuria. Metab Clin Exp 54:719–728CrossRefGoogle Scholar
Thimm E, Herebian D, Assmann B et al (2011) Increase of CSF tyrosine and impaired serotonin turnover in tyrosinemia type I. Mol Genet Metab 102:122–125CrossRefGoogle Scholar
Thimm E, Richter-Werkle R, Kamp G et al (2012) Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC. J Inherit Metab Dis 35:263–268CrossRefGoogle Scholar
Zatkova A (2011) An update on molecular genetics of alkaptonuria (AKU). J Inherit Metab Dis 34:1127–1136CrossRefGoogle Scholar