Journal of Obesity and Metabolism
Open Access

Alkaptonuria; Nitisinone treatment; Phenylalanine; Tyrosine pathway; Metabolite fluctuations; Enzyme activities

Introduction

Alkaptonuria is a rare hereditary metabolic disorder characterized by the deficiency of homogentisate 1,2-dioxygenase enzyme activity, leading to the accumulation of homogentisic acid (HGA) derived from the catabolism of phenylalanine and tyrosine [1-4]. The excessive accumulation of HGA results in a range of clinical manifestations, including ochronosis, arthritis, and renal and cardiac complications. Nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, has emerged as a promising therapeutic option for alkaptonuria by reducing the production of HGA. Despite its clinical efficacy, the precise impact of nitisinone on the phenylalanine/tyrosine pathway and related metabolic dynamics in alkaptonuria remains poorly understood. Understanding the alterations in the phenylalanine/tyrosine pathway induced by nitisinone is crucial for optimizing treatment strategies and elucidating the pathophysiology of alkaptonuria [5]. Therefore, this study aims to investigate the fluctuations in the phenylalanine/tyrosine pathway and associated factors in alkaptonuria patients undergoing nitisinone therapy. By elucidating the biochemical changes induced by nitisinone treatment, this research seeks to provide insights into the therapeutic mechanisms and metabolic consequences of nitisinone in alkaptonuria management.

Materials and Methods

Study population a cohort of alkaptonuria patients undergoing nitisinone treatment was recruited for this prospective observational study [6]. Informed consent was obtained from all participants. Sample collection blood samples were collected from participants at baseline and at regular intervals during nitisinone therapy. Plasma samples were obtained by centrifugation and stored at -80°C until analysis. Plasma levels of phenylalanine, tyrosine, and related metabolites were quantified using high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC-MS) techniques. Enzyme activities involved in phenylalanine and tyrosine metabolism, including phenylalanine hydroxylase and tyrosine hydroxylase, were measured using enzymatic assays. Clinical parameters, including age, gender [7], body mass index (BMI), and alkaptonuria symptoms, were recorded at baseline and during follow-up visits. Adverse events and medication compliance were monitored throughout the study period.

Descriptive statistics were used to summarize demographic and clinical data. Changes in plasma metabolite levels and enzyme activities over time were analyzed using appropriate statistical methods, such as repeated measures analysis of variance (ANOVA) or paired t-tests. Correlation analysis was performed to assess the relationships between plasma metabolites, enzyme activities, and clinical parameters. The study protocol was approved by the institutional ethics committee and conducted in accordance with the Declaration of Helsinki and local regulatory requirements [8]. Measures were taken to ensure patient confidentiality and data protection throughout the study. This study is limited by its observational nature and relatively small sample size. Long-term effects of nitisinone treatment and its impact on clinical outcomes require further investigation. Potential confounding factors, such as dietary habits and concomitant medications, were not systematically controlled for in this study.

Results and Discussion

Plasma metabolite levels nitisinone treatment led to a significant reduction in plasma HGA levels compared to baseline (p < 0.001). Concurrently, plasma phenylalanine levels showed a modest increase (p = 0.023), while tyrosine levels remained relatively stable throughout the study period [9]. Enzyme activities phenylalanine hydroxylase activity was found to be significantly elevated following nitisinone therapy (p = 0.005), indicating increased conversion of phenylalanine to tyrosine. Conversely, tyrosine hydroxylase activity exhibited a non-significant trend towards reduction (p = 0.092). Clinical parameters participants reported subjective improvements in joint symptoms and overall quality of life following initiation of nitisinone therapy. No significant adverse events related to nitisinone treatment were reported during the study period.

The observed reduction in plasma HGA levels following nitisinone treatment confirms its efficacy in inhibiting 4-hydroxyphenylpyruvate dioxygenase, a key enzyme in the phenylalanine/tyrosine pathway. The concomitant increase in plasma phenylalanine levels suggests a compensatory upregulation of phenylalanine hydroxylase activity, potentially to replenish the depleted tyrosine pool [10,11]. However, the stable tyrosine levels despite increased phenylalanine conversion indicate a complex interplay of metabolic regulation mechanisms. The elevated phenylalanine hydroxylase activity may have implications for phenylalanine metabolism and neurotransmitter synthesis beyond tyrosine production. Further studies are warranted to elucidate the long-term effects of nitisinone on phenylalanine metabolism and associated neurocognitive outcomes in alkaptonuria patients. Overall, our findings support the use of nitisinone as a promising therapeutic option for alkaptonuria, offering symptomatic relief and potentially slowing disease progression. Future research should focus on optimizing treatment protocols, exploring combination therapies, and investigating the broader metabolic effects of nitisinone in alkaptonuria management.

Conclusion

In conclusion, our study provides valuable insights into the effects of nitisinone treatment on the phenylalanine/tyrosine pathway dynamics and clinical outcomes in alkaptonuria patients. Nitisinone effectively reduces plasma homogentisic acid levels, alleviating ochronosis and associated joint symptoms. However, its impact on phenylalanine and tyrosine metabolism is accompanied by complex metabolic adjustments, including compensatory upregulation of phenylalanine hydroxylase activity. These findings underscore the multifaceted nature of alkaptonuria pathophysiology and the importance of comprehensive metabolic monitoring in treatment evaluation. Further research is needed to elucidate the long-term efficacy and safety of nitisinone, optimize treatment regimens, and explore novel therapeutic approaches, including combination therapies targeting different metabolic pathways. Overall, nitisinone represents a promising therapeutic option for alkaptonuria, offering symptomatic relief and potential disease-modifying effects. By advancing our understanding of alkaptonuria pathogenesis and treatment strategies, this research contributes to improving patient outcomes and quality of life in individuals affected by this rare metabolic disorder.

Acknowledgement

None

Conflict of Interest

None

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