Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK.
Department of Musculoskeletal Biology, University of Liverpool, L7 8TX, Liverpool, UK.
Sci Rep. 2019 Jul 11;9(1):10024. doi: 10.1038/s41598-019-46033-x.
Nitisinone decreases homogentisic acid (HGA) in Alkaptonuria (AKU) by inhibiting the tyrosine metabolic pathway in humans. The effect of different 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 five 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 significantly higher post-nitisinone (p < 0.0001) at all doses. Similarly, combined 24 hr urine:total body water ratios for all analytes were significantly higher post-nitisinone, compared with pre-nitisinone baseline for all doses (p = 0.0002 - p < 0.0001). Significantly 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 first time, experimental evidence of the metabolite pool that would otherwise be directed towards pigment formation, has been unmasked.
尼替西农通过抑制人体酪氨酸代谢途径降低尿黑酸症（AKU）中的同型半胱氨酸（HGA）。在四周的时间内，研究了不同剂量的尼替西农对 AKU 患者循环和 24 小时尿中苯丙氨酸（PA）、酪氨酸（TYR）、对羟苯丙酮酸（HPPA）、对羟苯乳酸（HPLA）和 HGA 的排泄的影响。40 名 AKU 患者随机分为五组，每组 8 名患者，每天接受 1、2、4 或 8mg 的尼替西农治疗，或不接受药物（对照）治疗。通过串联质谱法分析 24 小时尿液和用药前后采集的血清样本中的代谢物。校正血清代谢物的总水量，测定 24 小时尿液加总水量的 PA、TYR、HPPA、HPLA 和 HGA 代谢物的总和。通过 4 周的研究期间的体重和尿液尿素来检查饮食和新陈代谢的稳定性。尼替西农用药前后的尿液代谢物（PA、TYR、HPPA、HPLA 和 HGA）总和相似。尼替西农用药后所有剂量的总水量代谢物总和显著升高（p<0.0001）。同样，与尼替西农用药前基线相比，所有剂量的所有分析物的 24 小时尿液：总水量比值均显著升高（p=0.0002-p<0.0001）。尼替西农治疗后，观察到酪氨酸代谢途径的代谢物浓度呈剂量依赖性升高，我们推测，这是首次揭示了原本会导致色素形成的代谢物池的实验证据。
