Departments of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool University Hospitals NHS Foundation Trusts, Prescot Street, Liverpool, L7 8XP, UK.
William Henry Duncan Building, University of Liverpool, Liverpool, UK.
Sci Rep. 2022 Sep 27;12(1):16083. doi: 10.1038/s41598-022-20424-z.
Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701-900 (105), 901-1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.
尼替西农（NIT）会不可避免地引起不同程度的高酪氨酸血症。然而，人们对酪氨酸分解代谢途径中的动态适应关系的理解尚未得到充分研究。本研究的目的是评估蛋白质摄入量、血清 NIT（sNIT）和酪氨酸途径代谢物对高酪氨酸血症的影响在尿黑酸尿症（AKU）中。这些分析包括 SONIA 2 研究（尼替西农在尿黑酸尿症中的适用性 2）中第 3 个月（V2）、第 12 个月（V3）、第 24 个月（V4）、第 36 个月（V5）和第 48 个月（V6）时采集的血清和 24 小时尿液样本。在血清和尿液中，所有时间点均分析了高本胱氨酸酸（HGA）、酪氨酸（TYR）、苯丙氨酸（PHE）、对羟基苯丙酮酸（HPPA）、对羟苯乳酸（HPLA）和 sNIT。使用 60%的体重计算总体水（TBW）代谢物。将 24 小时尿液和 TBW 代谢物相加，得到总和值。所有统计分析均为事后分析。共分析了 307 个血清和 24 小时尿液采样点。V2 至 V6 时的血清 TYR 范围为 478 至 1983μmol/L，分为以下几组（括号内为采样点数量）： < 701（47）、701-900（105）、901-1100（96）和 > 1100（59）μmol/L。大多数采样点的值大于 900μmol/L。sPHE 随 sTYR 的升高而增加（p<0.001）。血清和 TBW 中的酪氨酸、HPPA 和 HPLA 随 sTYR 的升高而增加（p<0.001），而 HPLA/TYR 比值降低（p<0.0001）。在 NIT 治疗期间，观察到了一种适应性反应，以最小化 TYR 的形成。与 TYR 相比，HPPA 向 HPLA 的转化率降低，这似乎是决定高酪氨酸血症程度的最主要因素。
