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Khedr, M, Cooper, MS, Hughes, AT, Milan, AM, Davison, AS, Norman, BP, Sutherland, H, Jarvis, JC, Fitzgerald, R, Markinson, L, Psarelli, E-E, Ghane, P, Deutz, NEP, Gallagher, JA and Ranganath, LR (2020) Nitisinone causes acquired tyrosinosis in alkaptonuria. Journal of Inherited Metabolic Diseases. ISSN 1573-2665
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Abstract
For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC-induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight-threatening keratopathy. In the context of a non-lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l-[13 C9 ]tyrosine and l-[d8 ]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P < .001), suggesting that NTBC increases tyrosine not just in serum but also in tissues (ie, acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC-related acquired tyrosinosis which should be overcome to ensure the safe use of NTBC in AKU.
| Item Type: | Article |
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| Additional Information: | This is the peer reviewed version of the following article: Khedr, M, Cooper, MS, Hughes, AT, et al. Nitisinone causes acquired tyrosinosis in alkaptonuria. J Inherit Metab Dis. 2020; 1– 10., which has been published in final form at http://dx.doi.org/10.1002/jimd.12229. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
| Uncontrolled Keywords: | 1103 Clinical Sciences |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | Wiley |
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| Date Deposited: | 08 Apr 2020 09:32 |
| Last Modified: | 04 Sep 2021 07:30 |
| DOI or ID number: | 10.1002/jimd.12229 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/12680 |
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