Lock Edward A, Gaskin Peter, Ellis Martin, Provan William M, Smith Lewis L
Syngenta, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK.
Toxicol Appl Pharmacol. 2006 Aug 15;215(1):9-16. doi: 10.1016/j.taap.2006.01.015. Epub 2006 Mar 31.
2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.
2-(2-硝基-4-三氟甲基苯甲酰基)-环己烷-1,3-二酮（NTBC）是大鼠肝脏4-羟基苯丙酮酸双加氧酶（HPPD）的强效抑制剂，可导致酪氨酸血症和角膜混浊。作为对该药物安全性评估的一部分，我们研究了NTBC对比格犬、兔子和恒河猴酪氨酸血症程度和角膜病变产生的影响。对比格犬或兔子单次口服10 mg NTBC/kg会增加血浆和眼房水中酪氨酸的浓度，酪氨酸血症呈时间和剂量依赖性。在血浆酪氨酸达到峰值时，肝脏HPPD受到明显抑制，而对酪氨酸转氨酶（TAT）和尿黑酸氧化酶的活性影响较小。对比格犬每日口服NTBC，剂量分别为0.1、0.5、1.5和5 mg/kg/天，给药11周后角膜混浊发生率为34%，停药后混浊情况逆转。给药18周后，所有剂量水平下血浆和眼房水中的酪氨酸均升高。相比之下，兔子每日口服NTBC 6周，恒河猴每日口服NTBC 12周，剂量均为10 mg/kg/天，尽管酪氨酸值明显升高，但未出现角膜混浊的迹象。我们的研究表明，NTBC是兔子、比格犬以及由此推断的恒河猴肝脏HPPD的强效抑制剂，在所研究的所有物种中均会导致明显的酪氨酸血症，而只有比格犬出现角膜病变。暴露于NTBC的实验动物中角膜病变的产生似乎并非简单地与眼液中酪氨酸的浓度相关，其他尚未明确的因素似乎是引发组织损伤所必需的。
