Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria
Background: Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management. Patients and methods: Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AK...
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Elsevier
2022-03-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426922000064 |
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| author | L.R. Ranganath A.M. Milan A.T. Hughes A.S. Davison M. Khedr B.P. Norman G. Bou-Gharios J.A. Gallagher M. Gornall R. Jackson R. Imrich J. Rovensky M. Rudebeck B. Olsson |
| author_facet | L.R. Ranganath A.M. Milan A.T. Hughes A.S. Davison M. Khedr B.P. Norman G. Bou-Gharios J.A. Gallagher M. Gornall R. Jackson R. Imrich J. Rovensky M. Rudebeck B. Olsson |
| author_sort | L.R. Ranganath |
| collection | DOAJ |
| description | Background: Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management. Patients and methods: Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AKU), treated with 0, 1, 2, 4 and 8 mg nitisinone daily (n = 8), were studied over four weeks. Serum homogentisic acid (sHGA), tyrosine (sTYR), phenylalanine (sPHE), hydroxyphenylpyruvate (sHPPA), hydroxyphenyllactate (sHPLA) and nitisinone (sNIT) were measured at baseline and after four weeks. Results: sNIT showed a clear dose-proportional response. sTYR increased markedly but with less clear-cut dose responses after nitisinone. Fasting and average 24-h (Cav) sTYR responses were similar. Individual patient sTYR 24-h profiles showed significant fluctuations during nitisinone therapy. At week 4, sTYR, sHPPA and sHPPL all showed dose-related increases compared to V0, with the greatest difference between 1 and 8 mg nitisinone seen for HPLA, while there was no change from V0 in sPHE. sHGA decreased to values around the lower limit of quantitation. Discussion: There was sustained tyrosinaemia after four weeks of nitisinone therapy with significant fluctuations over the day in individual patients. Diet and degree of conversion of HPPA to HPLA may determine extent of nitisinone-induced tyrosinaemia. Conclusion: A fasting blood sample is recommended to monitor sTYR during nitisinone therapy Adaptations in HPPA metabolites as well as the inhibition of tyrosine aminotransferase could be contributing factors generating tyrosinaemia during nitisinone therapy. |
| first_indexed | 2024-12-13T13:04:47Z |
| format | Article |
| id | doaj.art-d0d0e7c619c64230a023ce8cb3ce5421 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-13T13:04:47Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-d0d0e7c619c64230a023ce8cb3ce54212022-12-21T23:44:51ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-03-0130100846Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuriaL.R. Ranganath0A.M. Milan1A.T. Hughes2A.S. Davison3M. Khedr4B.P. Norman5G. Bou-Gharios6J.A. Gallagher7M. Gornall8R. Jackson9R. Imrich10J. Rovensky11M. Rudebeck12B. Olsson13Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, UK; William Henry Duncan Building, University of Liverpool, UK; Corresponding author at: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK.Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, UK; William Henry Duncan Building, University of Liverpool, UKDepartments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, UKDepartments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, UKDepartments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, UKWilliam Henry Duncan Building, University of Liverpool, UKWilliam Henry Duncan Building, University of Liverpool, UKWilliam Henry Duncan Building, University of Liverpool, UKLiverpool Cancer Trials Unit, University of Liverpool, UKLiverpool Cancer Trials Unit, University of Liverpool, UKNational Institute of Rheumatic Diseases, Piešťany, Slovakia; Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, SlovakiaNational Institute of Rheumatic Diseases, Piešťany, SlovakiaOnPoint Science AB, Stockholm, SwedenGarriguella AB, Ekerö, SwedenBackground: Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management. Patients and methods: Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AKU), treated with 0, 1, 2, 4 and 8 mg nitisinone daily (n = 8), were studied over four weeks. Serum homogentisic acid (sHGA), tyrosine (sTYR), phenylalanine (sPHE), hydroxyphenylpyruvate (sHPPA), hydroxyphenyllactate (sHPLA) and nitisinone (sNIT) were measured at baseline and after four weeks. Results: sNIT showed a clear dose-proportional response. sTYR increased markedly but with less clear-cut dose responses after nitisinone. Fasting and average 24-h (Cav) sTYR responses were similar. Individual patient sTYR 24-h profiles showed significant fluctuations during nitisinone therapy. At week 4, sTYR, sHPPA and sHPPL all showed dose-related increases compared to V0, with the greatest difference between 1 and 8 mg nitisinone seen for HPLA, while there was no change from V0 in sPHE. sHGA decreased to values around the lower limit of quantitation. Discussion: There was sustained tyrosinaemia after four weeks of nitisinone therapy with significant fluctuations over the day in individual patients. Diet and degree of conversion of HPPA to HPLA may determine extent of nitisinone-induced tyrosinaemia. Conclusion: A fasting blood sample is recommended to monitor sTYR during nitisinone therapy Adaptations in HPPA metabolites as well as the inhibition of tyrosine aminotransferase could be contributing factors generating tyrosinaemia during nitisinone therapy.http://www.sciencedirect.com/science/article/pii/S2214426922000064AlkaptonuriaHomogentisic acidTyrosineHydroxyphenylpyruvateHydroxyphenyllactatePhenylalanine |
| spellingShingle | L.R. Ranganath A.M. Milan A.T. Hughes A.S. Davison M. Khedr B.P. Norman G. Bou-Gharios J.A. Gallagher M. Gornall R. Jackson R. Imrich J. Rovensky M. Rudebeck B. Olsson Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria Molecular Genetics and Metabolism Reports Alkaptonuria Homogentisic acid Tyrosine Hydroxyphenylpyruvate Hydroxyphenyllactate Phenylalanine |
| title | Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria |
| title_full | Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria |
| title_fullStr | Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria |
| title_full_unstemmed | Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria |
| title_short | Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria |
| title_sort | characterization of changes in the tyrosine pathway by 24 h profiling during nitisinone treatment in alkaptonuria |
| topic | Alkaptonuria Homogentisic acid Tyrosine Hydroxyphenylpyruvate Hydroxyphenyllactate Phenylalanine |
| url | http://www.sciencedirect.com/science/article/pii/S2214426922000064 |
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