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Quantification of the Flux of Tyrosine Pathway Metabolites During Nitisinone Treatment of Alkaptonuria

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Quantification of the Flux of Tyrosine Pathway Metabolites During Nitisinone Treatment of Alkaptonuria www.nature.com/scientificreports OPEN Quantifcation of the fux of tyrosine pathway metabolites during nitisinone treatment of Received: 21 August 2018 Accepted: 20 June 2019 Alkaptonuria Published: xx xx xxxx A. M. Milan 1,2, A. T. Hughes1,2, A. S. Davison 1,2, M. Khedr 1, J. Rovensky3, E. E. Psarelli4, T. F. Cox4, N. P. Rhodes2, J. A. Gallagher2 & L. R. Ranganath1,2 Nitisinone decreases homogentisic acid (HGA) in Alkaptonuria (AKU) by inhibiting the tyrosine metabolic pathway in humans. The efect of diferent daily doses of nitisinone on circulating and 24 h urinary excretion of phenylalanine (PA), tyrosine (TYR), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and HGA in patients with AKU was studied over a four week period. Forty AKU patients, randomised into fve groups of eight patients, received doses of 1, 2, 4 or 8 mg of nitisinone daily, or no drug (control). Metabolites were analysed by tandem mass spectrometry in 24 h urine and serum samples collected before and after nitisinone. Serum metabolites were corrected for total body water and the sum of 24 hr urine plus total body water metabolites of PA, TYR, HPPA, HPLA and HGA were determined. Body weight and urine urea were used to check on stability of diet and metabolism over the 4 weeks of study. The sum of quantities of urine metabolites (PA, TYR, HPPA, HPLA and HGA) were similar pre- and post-nitisinone. The sum of total body water metabolites were signifcantly higher post-nitisinone (p < 0.0001) at all doses. Similarly, combined 24 hr urine:total body water ratios for all analytes were signifcantly higher post-nitisinone, compared with pre-nitisinone baseline for all doses (p = 0.0002 – p < 0.0001). Signifcantly higher concentrations of metabolites from the tyrosine metabolic pathway were observed in a dose dependant manner following treatment with nitisinone and we speculate that, for the frst time, experimental evidence of the metabolite pool that would otherwise be directed towards pigment formation, has been unmasked. Alkaptonuria (AKU) (OMIM #203500) is caused by a genetic defciency of homogentisate dioxygenase (HGD) (EC 1.13.11.5), and is characterised by high circulating homogentisic acid (HGA)1,2. Excretion of HGA in the urine helps maintain lower circulating HGA but inevitably HGA is also converted to a pigment in body tissues through a process termed ochronosis1,2. Te excretion of HGA in urine tends to be protective, decreasing the bodily retention of HGA, except that its excretion can lead to kidney stones and renal failure3,4. Despite the efcient renal excretion of HGA, circulating HGA also remains measurable3,4. Circulating HGA can be oxidised via benzoquinone acetic acid to a brown-black pigment5. Tis pigment appears ochre-coloured under haematoxylin and eosin staining, leading to the term ochronotic pigment. Tis ochronotic pigment alters connective tissue properties leading to tissue breakdown6. Most of the devastating consequences of AKU in the form of premature arthritis, cardiac valve disease, osteoporosis, fractures, muscle, ligament and tendon ruptures are secondary to ochronosis7–9. Despite the crucial importance of ochronosis, little is known about the circulating concentration of HGA which results in pigmentation. Nitisinone inhibits p-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27), the enzyme leading to the forma- tion of HGA10,11 and has been used for more than twenty years in the treatment of hereditary tyrosinaemia type-1 (HT-1) (OMOM #276700)10,11. In AKU mice, nitisinone has been shown to decrease circulating HGA12,13 and to inhibit ochronosis12,13. Te decrease in HGA caused by nitisinone, both in serum and urine, is dose-dependent14. 1Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. 2Department of Musculoskeletal Biology, University of Liverpool, L7 8TX, Liverpool, UK. 3National Institute of Rheumatic Diseases, Piestany, Slovakia. 4Liverpool Cancer Trials Unit, University of Liverpool, Block C, Waterhouse Building, Liverpool, L69 3GL, UK. Correspondence and requests for materials should be addressed to A.M.M. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:10024 | https://doi.org/10.1038/s41598-019-46033-x 1 www.nature.com/scientificreports/ www.nature.com/scientificreports HGA and tyrosine concentrations have been quantifed in AKU before and afer treatment with nitisinone in the dose-response study SONIA 1 (Suitability of Nitisinone in Alkaptonuria)14. It is clear that HGA, afer being formed, can either be excreted in the urine, remain elevated in total body water, be tissue bound or be converted to ochronotic pigment. By blocking or reducing the formation of HGA, nitisinone should therefore decrease urinary HGA, total body water HGA as well as HGA-pigment polymer. Te aim of this study was to determine if the amounts of excreted metabolites (urinary) and total body water tyrosine metabolites (circulating) changed on nitisinone therapy, thereby reducing the load potentially directed towards pigment formation. We have tested this hypothesis in AKU patients with diferent doses of nitisinone as part of the SONIA 1 trial14. Subjects and Methods Te study was a randomised, open-label, parallel-group design with a no-treatment control group. Patients were randomised to receive either 1 mg, 2 mg, 4 mg or 8 mg nitisinone once daily or no treatment (control). Forty patients were randomised, equally distributed among the groups (eight patients per group; stratifed by each study centre using randomly permutated blocks). Te treatment period was of 4 weeks duration, during which the study drug, nitisinone, was administered. No details of dose, TYR or HGA results were available to medical monitors, sponsor personnel or study site personnel until study completion. Further details of the SONIA 1 study have been published in full elsewhere14. Patients were requested to maintain stable dietary habits during the 4-week study period in order not to change their dietary protein intake and to maintain a stable weight. Body weights were measured at each visit to provide an indication of change in diet or health (catabolism). Urine urea nitrogen was also calculated from urea measurements to further confrm that diet and health were stable over the 4 weeks of study. Urine creatinine measurements in patients across visits were checked to ensure that any diferences in metabolites were not due to diferences in efciency of urine collection. Twenty four hour serum profles of TYR were also measured to determine whether there was signifcant diurnal variation. Te choice of daily doses used in the present study, namely 0, 1, 2, 4 and 8 mg, was based on previous expe- rience and gaps that existed regarding the HGA-lowering efect of nitisinone in AKU15. Te investigational medicinal product, a 4 mg/mL suspension of nitisinone (Orfadin, Sweden) was administered in the morning and allowed easy administration of the selected doses. Te daily dosing frequency in our study was based on the long half-life of nitisinone. Written consent was obtained from all patients before any study procedures. An external data and safety mon- itoring board was assigned to evaluate the safety data. Chemical analysis. Urine sample collection and handling. At baseline, and week 4, urine was collected over 24 h into 2.5 L bottles containing 30 mL of 5 N sulphuric acid and stored away from bright light in cool con- ditions. Te weight of the collected urine was recorded and used as the volume in the calculations of 24 hr urine excretion assuming a density of 1 g/mL. Aliquots of the urine were frozen and retained at −80 °C until analysis. Measurements of 24-hour urine PA, TYR, HPPA, HPLA and HGA concentrations (designated uPA24, uTYR24, uHPPA24, uHPLA24 and uHGA24) were performed at baseline (week 0) and week 4. Serum sample collection and handling. Measurement of serum PA, TYR, HPPA, HPLA and HGA concentrations (designated sPA, sTYR, sHPPA, sHPLA and sHGA) were performed at baseline (week 0) and week 4. At each visit, one sample was collected pre-dose in fasting patients. Blood samples were collected in plain serum tubes (Sarstedt, Germany). An aliquot of serum was immediately acidifed using perchloric acid (10% v/v 5.8 M), based on previous experience16,17 of stabilising HGA, and kept frozen at −80 °C until analysis. Serum samples were collected across a 24 hour period at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18 and 24 hours (8am was time zero as a fasting baseline) at week 0 and at week 4, from all 40 patients. Serum was processed as described above. Samples from Piestany were transported frozen by courier to Liverpool and all biochemical analyses were performed in the Department of Clinical Biochemistry, Liverpool Clinical Laboratories, Royal Liverpool and Broadgreen University Hospital NHS Trust. Analyses of PA, TYR, HPPA, HPLA and HGA. Te concentrations of PA, TYR, HPPA, HPLA and HGA in serum and urine were measured by liquid chromatography tandem mass spectrometry16,18. The published method was further validated to include PA, HPPA and HPLA (unpublished data). All analyses were performed on an Agilent 6490 Triple Quadrupole mass spectrometer with Jet-Stream electrospray ionisation coupled with an Agilent 1290 Infnity II Ultra High Performance Liquid Chromatography pump and autosampler. Briefy this method incorporates reverse-phase chromatographic separation on an Atlantis dC18 column (100 mm × 3.0mm, 3 µm, Waters); initial chromatographic conditions of 80:20 water:methanol with 0.1% formic acid (v/v) increased linearly to 10:90 over 5 min. Matrix-matched calibration standards and quality controls were used with appropri- ate isotopically-labelled internal standards with quantitation in multiple reaction mode (PA and TYR in positive ionisation and HPPA, HPLA and HGA in negative ionisation). Sample preparation was by dilution in a combined 13 internal standard solution containing C6-HGA, d4-TYR and d5-PA in 0.1% formic acid (v/v) in deionised water.
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