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.