title: The effect of a low-protein diet and dietary supplementation of threonine on tyrosine and 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione-induced corneal lesions, the extent of tyrosinemia, and the activity of enzymes involved in tyrosine catabolism in the rat.
abstract: Rats fed a low-protein diet and administered 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC) orally at 30 mumol/kg/day (10 mg/kg/day) or fed a low-protein diet containing 5 ppm NTBC develop lesions to the cornea of the eye within 3-8 days of exposure with an incidence of about 80%. This treatment also produces a marked inhibition of both hepatic and renal 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity, an induction of hepatic but not renal tyrosine amino transferase activity, and a marked tyrosinemia in the plasma and aqueous humor. The extent of tyrosinemia and changes in the activity of tyrosine catabolic enzymes are similar to those reported for rats fed a normal protein diet and administered NTBC orally at 30 mumol/kg/day. However, the onset of corneal lesions occurs much earlier in rats fed a low-protein diet. The adverse ocular effects of NTBC can be alleviated by supplementing the low-protein diet with 1% w/w threonine. The protection afforded by threonine inclusion in the diet was not due to any amelioration in the extent of inhibition of hepatic HPPD activity or reduction in the extent of the tyrosinemia as measured 8 days after treatment. Rats fed L-tyrosine at 5% w/w in a low-protein diet rapidly develop lesions to the cornea of the eye, which are associated with a marked tyrosinemia, increased hepatic tyrosine aminotransferase activity, and about a 50% reduction in the activity of hepatic HPPD. The onset of corneal lesions produced by feeding a high tyrosine diet could be delayed, but not prevented, by inclusion of 1% w/w threonine in the low-protein diet. The basis for the beneficial effect of dietary supplementation of threonine in alleviating the corneal lesions produced by NTBC is unclear. However, our findings do illustrate that protein deficiency limits the ability of the rat to respond to a tyrosine load produced by inhibition of HPPD.
authors.affiliation: Zeneca Central Toxicology Laboratory, Cheshire, United Kingdom. Ted.Lock@ctl.zeneca.com
authors.forename: E A
authors.initials: EA
authors.lastname: Lock
authors.forename: P
authors.initials: P
authors.lastname: Gaskin
authors.forename: M K
authors.initials: MK
authors.lastname: Ellis
authors.forename: M
authors.initials: M
authors.lastname: Robinson
authors.forename: W M
authors.initials: WM
authors.lastname: Provan
authors.forename: L L
authors.initials: LL
authors.lastname: Smith
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D003316:Corneal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D003512:Cyclohexanones / Q000633:toxicity*; D004044:Dietary Proteins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000494:pharmacology; D009579:Nitrobenzoates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013912:Threonine / Q000494:pharmacology*; D014443:Tyrosine / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D003512:Cyclohexanones; D004044:Dietary Proteins; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D013912:Threonine; D014443:Tyrosine; D008715:Methionine; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone