Tissue distribution of 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) and its effect on enzymes involved in tyrosine catabolism in the mouse.
Administration of a single oral dose of 2-(2-nitro-4-trifluoromethyl-benzoyl)-cyclohexane-1,3-dione (NTBC) to mice increases the concentration of tyrosine in the plasma and aqueous humour. The tyrosinaemia is both time and dose-dependent with a single dose of 30 micromol NTBC/kg (10 mg/kg) producing maximal concentrations of tyrosine in plasma of about 1200 nmol/ml and in aqueous humour of about 2200 nmol/ml at 16 h after dosing. Analysis of the key hepatic enzymes involved in tyrosine catabolism, following a single dose of 30 micromol 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 tyrosine aminotransferase (TAT) was induced about two-fold, while the activity of hepatic homogentisic acid oxidase (HGO) was reduced at 4 and 5 days after dosing. Daily oral administration of NTBC at doses up to 480 micromol NTBC/kg (160mg/kg/day) to mice produced a maximal tyrosinaemia of about 600-700nmol/ml plasma, 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 [14C]-NTBC at 30 micromol/kg led to selective retention of radiolabel in the liver and to a lesser extent the kidneys. Our studies show that NTBC is a potent inhibitor of mouse liver HPPD, which following repeat exposure produces a marked and persistent tyrosinaemia, which does not result in ocular toxicity.
Lock
E A
EA
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK. ted.lock@ctl.astrazeneca.com
Gaskin
P
P
Ellis
M K
MK
McLean Provan
W
W
Robinson
M
M
Smith
L L
LL
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000378:metabolism*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D003512:Cyclohexanones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D049308:Dioxygenases; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005123:Eye / Q000378:metabolism; D050560:Homogentisate 1,2-Dioxygenase; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009579:Nitrobenzoates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010105:Oxygenases / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014443:Tyrosine / Q000097:blood / Q000378:metabolism*
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D010105:Oxygenases; D049308:Dioxygenases; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D050560:Homogentisate 1,2-Dioxygenase; C077073:nitisinone