Tissue distribution of 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) and its effect on enzymes involved in tyrosine catabolism inthe mouse

Administration of a single oral dose of 2-(2-nitro-4-trifluoromethyl-benzoy l)-cyclohexane-1,3-dione (NTBC) to mice increases the concentration of tyro sine in the plasma and aqueous humour. The tyrosinaemia is both time and do se-dependent with a single dose of 30 mu mol NTBC/kg (10 mg/kg) producing m aximal concentrations of tyrosine in plasma of about 1200 nmol/ml and in aq ueous humour of about 2200 nmol/ml at 16 h after dosing. Analysis of the ke y hepatic enzymes involved in tyrosine catabolism. following a single dose of 30 mu mol NTBC/kg, showed that 4-hydroxyphenylpyruvate dioxygenase (HPPD ) was markedly inhibited soon after dosing and that the activity recovered very slowly. In response to the tyrosinaemia, the activity of hepatic tyros ine aminotransferase (TAT) was induced about two-fold, while the activity o f hepatic homogentisic acid oxidase (HGO) was reduced at 4 and 5 days after dosing. Daily oral administration of NTBC at doses up to 480 mu mol NTBC/k g (160mg/kg/day) to mice produced a maximal tyrosinaemia of about 600-700nm ol/ml plasmal showing some adaptation relative to a single dose. Unlike the rat, no treatment-related corneal lesions of the eye were seen at any dose levels up to 6 weeks. Administration of a single oral dose of [C-14]-NTBC at 30 mu mol/kg led to selective retention of radiolabel in the liver and t o a lesser extent the kidneys. Our studies show that NTBC is a potent inhib itor of mouse liver HPPD, which following repeat exposure produces a marked and persistent tyrosinaemia, which does not result in ocular toxicity. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.