Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice
Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice
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DOI：
10.1016/j.reprotox.2007.05.006
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Kato, Ikuo
中科院分区：
文献类型：
--
作者：
Fukushima, Ryou;Kanamori, Susumu;Kato, Ikuo
来氟米特是一种免疫抑制剂，可抑制嘧啶核苷酸的从头合成和蛋白酪氨酸激酶的活性。本研究检查了来氟米特在小鼠中的致畸性。从妊娠第6天至第15天，以10、30或70 mg/kg/天的剂量经口给药妊娠小鼠。在70 mg/kg剂量下，所有胚胎均被吸收，未检测到活胎。在30 mg/kg时，来氟米特降低了胎儿的存活率，并增加了多发性外部、骨骼和内脏畸形的发生率。特征性外部畸形为神经管缺陷、腭裂和尾部畸形。在少数胎儿中观察到肢体畸形。骨骼检查发现颈椎至骶椎、肋骨和胸骨畸形。内脏畸形主要为室间隔膜部缺损和永存动脉干。本研究的结果表明，在妊娠第6至15天给予来氟米特30 mg/kg可诱导小鼠颅面畸形以及中轴骨骼、心脏和大血管畸形。(C)2007年由Elsevier Inc.出版
Leflunomide is an immunosuppressive agent that inhibits de novo synthesis of pyrimidine nucleotides and the activity of protein tyrosine kinase. This study examined the teratogenicity of Leflunomide in mice. Pregnant mice were treated orally with Leflunomide at a dose of 10, 30 or 70 mg/kg/day from day 6 to 15 of pregnancy. At 70 mg/kg, all embryos were resorbed and no live fetuses were detected. At 30 mg/kg, Leflunomide reduced fetal viability, and increased the incidence of multiple external, skeletal and visceral malformations. Characteristic external malformations were neural tube defects, cleft palate and tail deformities. Limb malformations were observed in a small number of fetuses. Skeletal examinations revealed malformations of cervical to sacral vertebrae, ribs and sternebrae. In the viscerae, the main anomalies were membranous ventricular septum defect and persistent truncus arteriosus. The results of this study indicate that Leflunomide administered at 30 mg/kg on days 6 to 15 of pregnancy can induce craniofacial malformations and deformities of the axial skeleton, heart and great vessels in mice. (C) 2007 Published by Elsevier Inc.