Caldwell J, Anthony A, Cotgreave I A, Sangster S A, Sutton J D, Bernard B K, Ford R A
Food Chem Toxicol. 1985 Jun;23(6):559-66. doi: 10.1016/0278-6915(85)90179-6.
Cinnamyl anthranilate is a synthetic food flavouring and fragrance agent, formerly used at very low levels. There is currently some concern over the potential risk to man from its use, since it has been found to cause liver tumours in mice, following the administration of very large doses. This paper reports studies of its disposition and hepatic effects in B6C3F1 mice in relation to dose. Following a single oral dose of 500 mg cinnamyl anthranilate/kg body weight to B6C3F1 mice peak plasma levels of unchanged compound were reached in 30 min, and were higher in males than in females. Unchanged cinnamyl anthranilate in the urine accounted for 0.3-0.4% of the dose. Anthranilic acid (c. 17%) and hippuric acid (35%; the major metabolite of cinnamyl alcohol) were present in the urine, and recoveries of both were higher in females. Groups of male and female B6C3F1 mice were given 0, 10, 100, 1000, 5000, 15,000 and 30,000 ppm cinnamyl anthranilate in the diet. After 4 days, the diet was removed and urine collected for 24 hr. This contained cinnamyl anthranilate (more in males) hippuric and anthranilic acids (more in females) in concentrations that increased with dose. Other animals were given these diets for 19 days and then killed. Relative liver weight and hepatic microsomal cytochrome P-450 increased with increasing dose above 1000 ppm cinnamyl anthranilate, more markedly in males than in females although the maximum response (roughly twofold) was very similar in the two sexes. SDS-PAGE examination of the microsomes revealed the induction of a cytochrome P-450 isozyme of 53.1 kDa, but the aniline hydroxylase and p-nitroanisole O-demethylase activities of the 9000 g supernatant of liver were not induced. The data are discussed in terms of their significance for the human safety evaluation of cinnamyl anthranilate. It is important to note that liver hypertrophy, microsomal enzyme induction and the excretion of unchanged cinnamyl anthranilate all have the same dose-threshold for their appearance. This suggests that the hepatic effects of cinnamyl anthranilate may be mediated by unhydrolysed cinnamyl anthranilate, which is present only at very high doses due to the saturation of its hydrolysis.
邻氨基苯甲酸肉桂酯是一种合成食用香料和芳香剂，以前使用量极低。目前人们对其使用给人类带来的潜在风险有所担忧，因为在给小鼠大剂量给药后，已发现它会导致小鼠患肝癌。本文报告了在B6C3F1小鼠中，该物质的处置情况及其肝脏效应与剂量的关系。给B6C3F1小鼠单次口服500毫克邻氨基苯甲酸肉桂酯/千克体重后，30分钟内血浆中未变化的化合物达到峰值水平，且雄性小鼠的峰值水平高于雌性小鼠。尿液中未变化的邻氨基苯甲酸肉桂酯占给药剂量的0.3 - 0.4%。尿液中存在邻氨基苯甲酸（约17%）和马尿酸（35%；肉桂醇的主要代谢产物），且雌性小鼠中这两种物质的回收率更高。给雄性和雌性B6C3F1小鼠分组喂食含0、10、100、1000、5000、15000和30000 ppm邻氨基苯甲酸肉桂酯的饲料。4天后，移除饲料并收集24小时尿液。尿液中含有邻氨基苯甲酸肉桂酯（雄性小鼠中含量更多）、马尿酸和邻氨基苯甲酸（雌性小鼠中含量更多），其浓度随剂量增加而升高。其他动物喂食这些饲料19天后处死。当邻氨基苯甲酸肉桂酯剂量高于1000 ppm时，相对肝脏重量和肝脏微粒体细胞色素P - 450随剂量增加而升高，雄性小鼠比雌性小鼠更明显，尽管两性的最大反应（约两倍）非常相似。对微粒体进行十二烷基硫酸钠 - 聚丙烯酰胺凝胶电泳分析显示，诱导出了一种53.1 kDa的细胞色素P - 450同工酶，但肝脏9000 g上清液的苯胺羟化酶和对硝基苯甲醚O - 脱甲基酶活性未被诱导。本文根据这些数据对邻氨基苯甲酸肉桂酯的人体安全性评估的意义进行了讨论。需要注意的是，肝脏肥大、微粒体酶诱导以及未变化的邻氨基苯甲酸肉桂酯的排泄出现的剂量阈值相同。这表明邻氨基苯甲酸肉桂酯对肝脏的影响可能是由未水解的邻氨基苯甲酸肉桂酯介导的，由于其水解饱和，只有在非常高的剂量下才会存在未水解的邻氨基苯甲酸肉桂酯。
