Nitisinone causes acquired tyrosinosis in alkaptonuria

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‐[13C9]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.

Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria

“…In the present study, the peak of sHGA and sTYR was delayed compared to sNIT because they are protein intake-mediated, and reflect continuing intestinal PHE and TYR absorption. The increased fluctuations in sTYR during NIT treatment, compared to those before NIT administration, is probably due to HPPD inhibition [8] .…”

“…Inhibition of HPPD however, not only prevents conversion of hydroxyphenylpyruvate (HPPA) to HGA but also leads to accumulation of metabolites proximal to this inhibition [7] . Massive tyrosinaemia results from HPPD inhibition leading to deleterious effects such as corneal keratopathy [6] , [8] , [9] . Further, tyrosinaemia is possibly associated with the cognitive impairment observed in children when nitisinone is used as life-saving therapy in hereditary tyrosinaemia type 1 (HT-1) (OMIM# 276700 ), although the causative mechanisms of this impairment are not yet fully understood [10] , [11] ..…”

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

“…Nitisinone lowers HGA but increases circulating and tissue tyrosine levels. 25 Direct comparison of sTYR between matched SONIA 2 and NAC visits showed lower levels in the NAC. There were also fewer keratopathies in the NAC, due to active management of the diet and possibly the lower dose.…”

Vitiligo, alkaptonuria, and nitisinone—A report of three families and review of the literature

“…Decrease in HGA after nitisinone could decrease this protection against oxidant stress, increasing the vulnerability to vitiligo. Additionally, following administration of nitisinone, the inhibition of 4‐hydroxyphenylpyruvate dioxygenase results in a marked increase in serum and tissue tyrosine 28 . Since the usual metabolism of tyrosine through HGA is interrupted, increased flux along alternate pathways results.…”