Lock E A, Gaskin P, Ellis M K, Robinson M, Provan W M, Smith L L
Zeneca Central Toxicology Laboratory, Cheshire, United Kingdom.
Toxicol Appl Pharmacol. 1998 May;150(1):125-32. doi: 10.1006/taap.1998.8404.
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.
给大鼠喂食低蛋白饮食，并以30 μmol/kg/天（10 mg/kg/天）的剂量口服2-(2-硝基-4-三氟甲基苯甲酰基)环己烷-1,3-二酮（NTBC），或者喂食含有5 ppm NTBC的低蛋白饮食，在接触后3 - 8天内，约80%的大鼠眼部角膜会出现病变。这种处理还会显著抑制肝脏和肾脏的4-羟基苯丙酮酸双加氧酶（HPPD）活性，诱导肝脏而非肾脏的酪氨酸氨基转移酶活性，并使血浆和房水中出现明显的酪氨酸血症。酪氨酸血症的程度以及酪氨酸分解代谢酶活性的变化与给正常蛋白饮食的大鼠口服30 μmol/kg/天NTBC时所报道的情况相似。然而，在喂食低蛋白饮食的大鼠中，角膜病变的出现要早得多。通过在低蛋白饮食中添加1% w/w的苏氨酸，可以减轻NTBC对眼睛的不良影响。饮食中添加苏氨酸所提供的保护作用并非由于治疗8天后肝脏HPPD活性抑制程度的任何改善或酪氨酸血症程度的降低。在低蛋白饮食中喂食5% w/w L-酪氨酸的大鼠会迅速出现眼部角膜病变，这与明显的酪氨酸血症、肝脏酪氨酸氨基转移酶活性增加以及肝脏HPPD活性降低约50%有关。通过在低蛋白饮食中添加1% w/w的苏氨酸，可以延迟但不能预防高酪氨酸饮食引起的角膜病变的发生。饮食补充苏氨酸在减轻NTBC引起的角膜病变方面产生有益作用的基础尚不清楚。然而，我们的研究结果确实表明，蛋白质缺乏会限制大鼠对HPPD抑制产生的酪氨酸负荷的反应能力。
