Born S L, Fix A S, Caudill D, Lehman-McKeeman L D
Research Institute for Fragrance Materials, Hackensack, New Jersey, 07601, USA.
Toxicol Appl Pharmacol. 1998 Jul;151(1):45-56. doi: 10.1006/taap.1998.8442.
Coumarin is a known hepatotoxicant in laboratory animals, particularly rats. However, the mouse lung was identified as a major target organ in a chronic bioassay, with an oral gavage dosage of 200 mg/kg coumarin increasing the incidence of alveolar/bronchiolar adenomas and carcinomas. The purpose of the present work was to determine whether coumarin was acutely toxic in the mouse and rat lung. Male and female B6C3F1 mice were dosed orally by gavage with coumarin at 0, 10, 20, 50, 100, 150, and 200 mg/kg and lung toxicity was determined 24 h later by histological evaluation. The results indicated that coumarin dosages >/= 150 mg/kg caused selective injury to Clara cells in the distal bronchiolar epithelium. The time course of this injury was studied from 6 h to 7 days after a single dosage of coumarin (200 mg/kg). At 12 h after dosing, Clara cell swelling was apparent along with the onset of necrosis and bronchiolar epithelial disorganization. At 24-48 h, necrotic Clara cells were observed sloughed into the lumens of the terminal bronchioles, with concomitant thinning of the epithelium and flattening of the remaining ciliated cells. By 72-96 h, there was epithelial hypertrophy and hyperplasia, and by 7 days after dosing, the Clara cells had regenerated and the bronchiolar epithelial architecture appeared nearly normal. Unlike the mouse, oral administration of coumarin (200 mg/kg) caused severe hepatotoxicity in male F344 rats, seen histologically as centrilobular necrosis and associated with increases, up to 140-fold, in serum ALT, AST, and SDH levels. Clara cell toxicity was not observed in the distal bronchioles of treated rats. However, in the upper airways, coumarin treatment produced generalized epithelial necrosis involving both ciliated and nonciliated cells. 3,4-Dihydrocoumarin (DHC), which is not a mouse lung carcinogen, did not cause Clara cell injury when dosed to mice at 800 mg/kg. This finding suggests, because DHC lacks a 3,4-double bond, that bioactivation of coumarin to a 3,4-epoxide intermediate may contribute to mouse lung Clara cell toxicity. Collectively, the results indicate that coumarin is a Clara cell toxicant and establish the mouse lung as a target organ for coumarin toxicity. These new findings lay the foundation for studies to determine the mechanisms of coumarin-induced toxicity and carcincogenicity and to define the relevance of these effects to humans.
香豆素在实验动物尤其是大鼠中是一种已知的肝毒性物质。然而，在一项慢性生物测定中，小鼠肺被确定为主要靶器官，经口灌胃给予200mg/kg香豆素会增加肺泡/细支气管腺瘤和癌的发生率。本研究的目的是确定香豆素对小鼠和大鼠肺是否具有急性毒性。给雄性和雌性B6C3F1小鼠经口灌胃给予0、10、20、50、100、150和200mg/kg的香豆素，24小时后通过组织学评估确定肺毒性。结果表明，香豆素剂量≥150mg/kg会对远端细支气管上皮中的克拉拉细胞造成选择性损伤。在单次给予香豆素（200mg/kg）后6小时至7天研究了这种损伤的时间进程。给药后12小时，克拉拉细胞肿胀明显，同时出现坏死和细支气管上皮紊乱。在24 - 48小时，观察到坏死的克拉拉细胞脱落到终末细支气管腔内，同时上皮变薄，其余纤毛细胞扁平。到72 - 96小时，出现上皮肥大和增生，给药后7天，克拉拉细胞再生，细支气管上皮结构几乎恢复正常。与小鼠不同，经口给予香豆素（200mg/kg）会导致雄性F344大鼠出现严重的肝毒性，组织学上表现为小叶中心坏死，并伴有血清ALT、AST和SDH水平升高至140倍。在接受治疗的大鼠远端细支气管中未观察到克拉拉细胞毒性。然而，在上呼吸道，香豆素治疗导致包括纤毛和非纤毛细胞在内的广泛性上皮坏死。3,4 - 二氢香豆素（DHC）不是小鼠肺癌致癌物，以800mg/kg剂量给小鼠给药时不会导致克拉拉细胞损伤。这一发现表明，由于DHC缺乏3,4 - 双键，香豆素生物活化形成3,4 - 环氧化合物中间体可能导致小鼠肺克拉拉细胞毒性。总体而言，结果表明香豆素是一种克拉拉细胞毒物，并确定小鼠肺是香豆素毒性的靶器官。这些新发现为确定香豆素诱导毒性和致癌性的机制以及确定这些效应与人类的相关性的研究奠定了基础。
