Born S L, Api A M, Ford R A, Lefever F R, Hawkins D R
Research Institute for Fragrance Materials, Inc., 2 University Plaza, Suite 406, Hackensack, NJ 07601, USA.
Food Chem Toxicol. 2003 Feb;41(2):247-58. doi: 10.1016/s0278-6915(02)00227-2.
Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara cell death, resulted in a statistically significant increased incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. In contrast, mouse lung tumors were not observed at the 100 and 50 mg/kg dose levels in the oral gavage study, or in CD-1 mice following chronic intake of coumarin at levels equivalent to 276 mg/kg in diet. The current studies were designed to determine the impact of oral gavage vs dietary administration on the pharmacokinetics and metabolism of coumarin in CD-1 and B6C3F1 mice and F344 rats. Following the administration of 200 mg/kg 14C-coumarin via oral gavage, lung C(max) values (total 14C-associated radioactivity) were five- and 37-fold greater than those resulting from a 50 mg/kg oral gavage dose or 1000 ppm in diet, respectively. Coumarin (200 mg/kg) pharmacokinetics and metabolism was also examined in F344 rats following oral gavage dosing. Total 14C-coumarin associated radioactivity in plasma was 3.5-fold lower than in the mouse, and the plasma half-life in rats was five-times longer than in mice. Using non-radiolabeled compound (200 mg/kg), coumarin and products of the coumarin 3,4-epoxidation pathway were quantitated in plasma and urine after oral gavage administration to mice and rats. 7-Hydroxycoumarin (7-HC) was quantitated in mouse plasma and urine. o-Hydroxyphenylacetic acid (o-HPAA) reached a concentration of 37 microg/ml in plasma, and accounted for 41% of the dose in the urine, whereas the C(max) for 7-hydroxycoumarin was 3 microg/ml, and represented 7% of the administered dose. In the rat, the plasma C(max) for o-HPAA was 6 microg/ml, and accounted for 12% of the dose. The coumarin C(max) in rat plasma was comparable to that in mouse. Coumarin 3,4-epoxide (CE) and its rearrangement product o-hydroxyphenylacetaldehyde (o-HPA) and o-hydroxyphenylethanol (o-HPE), were not detected at any time point in plasma or urine. This analysis of coumarin and CE pharmacokinetics in rodents suggests that the differential tumor response in the mouse oral gavage and dietary bioassays is a function of the route of exposure, whereas species differences in lung toxicity between mice and rats result from heightened local bioactivation in the mouse lung.
香豆素是一种公认的大鼠肝毒性物质，它还会导致小鼠肺部终末细支气管克拉拉细胞发生急性、选择性坏死。此外，以200mg/kg的剂量对小鼠进行香豆素慢性灌胃给药（该剂量会导致克拉拉细胞死亡），结果显示B6C3F1小鼠肺泡/细支气管腺瘤和癌的发病率显著增加。相比之下，在灌胃研究中，100mg/kg和50mg/kg剂量水平未观察到小鼠肺部肿瘤，在CD-1小鼠中，以相当于饮食中276mg/kg的水平长期摄入香豆素也未观察到肺部肿瘤。当前的研究旨在确定灌胃给药与饮食给药对CD-1小鼠、B6C3F1小鼠和F344大鼠体内香豆素的药代动力学和代谢的影响。经灌胃给予200mg/kg的14C-香豆素后，肺部的C(max)值（与14C相关的总放射性）分别比50mg/kg灌胃剂量或饮食中1000ppm剂量所产生的值高5倍和37倍。在对F344大鼠进行灌胃给药后，也研究了香豆素（200mg/kg）的药代动力学和代谢情况。血浆中与14C-香豆素相关的总放射性比小鼠低3.5倍，大鼠的血浆半衰期比小鼠长5倍。使用非放射性标记化合物（200mg/kg），在对小鼠和大鼠进行灌胃给药后，对血浆和尿液中的香豆素及其3,4-环氧化途径的产物进行了定量分析。在小鼠血浆和尿液中对7-羟基香豆素（7-HC）进行了定量分析。邻羟基苯乙酸（o-HPAA）在血浆中的浓度达到37μg/ml，占尿液中剂量的41%，而7-羟基香豆素的C(max)为3μg/ml，占给药剂量的7%。在大鼠中，o-HPAA的血浆C(max)为6μg/ml，占剂量的12%。大鼠血浆中的香豆素C(max)与小鼠相当。在血浆或尿液的任何时间点均未检测到香豆素3,4-环氧化物（CE）及其重排产物邻羟基苯乙醛（o-HPA）和邻羟基苯乙醇（o-HPE）。对啮齿动物体内香豆素和CE药代动力学的分析表明，小鼠灌胃和饮食生物测定中不同的肿瘤反应是暴露途径作用的结果，而小鼠和大鼠肺部毒性的种属差异是由于小鼠肺部局部生物活化增强所致。
