Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the Hedgehog signaling antagonist cyclopamine in the mouse
Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the Hedgehog signaling antagonist cyclopamine in the mouse
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DOI：
10.1093/toxsci/kfn076
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发表时间：
2008-07-01
影响因子：
3.8
通讯作者：
Bushman, Wade
中科院分区：
文献类型：
--
作者：
Lipinski, Robert J.;Hutson, Paul R.;Bushman, Wade
Hedgehog（Hh）信号通路是胚胎发育的重要调节因子，似乎在产后修复、癌症进展和转移中发挥重要作用。致畸的藜芦生物碱环巴胺是一种有效的Hh拮抗剂，并在体外和体内实验中用于研究Hh信号在不同生物过程中的作用。在这里，我们着手建立环巴胺诱导的致畸性小鼠的管理方案。通过小鼠全胚胎培养试验在体外测定环巴胺的畸形发生浓度为2.0 μ M。我们给雌性C57 BL/6 J小鼠不同剂量的环巴胺，通过口服灌胃，ip注射，或渗透泵输注，并评估毒性和药代动力学（PK）模型。推注给药受到毒性和快速清除的限制。以160 mg/kg/天的剂量在体内输注环巴胺产生的母鼠血清稳态浓度近似于2 μ M，相应的羊水浓度约为1.5 μ M。在30%的环巴胺暴露窝仔中诱导了大体面部缺陷，受影响的胚胎表现出唇腭裂。这是第一份报告，描述了PK和致畸潜力的环巴胺在小鼠中，并证明了短暂的Hh信号传导抑制诱导面部分裂异常的小鼠，模仿常见的人类出生缺陷。
The Hedgehog (Hh) signaling pathway is an essential regulator of embryonic development and appears to play important roles in postnatal repair and cancer progression and metastasis. The teratogenic Veratrum alkaloid cyclopamine is a potent Hh antagonist and is used experimentally both in vitro and in vivo to investigate the role of Hh signaling in diverse biological processes. Here, we set out to establish an administration regimen for cyclopamine-induced teratogenicity in the mouse. The dysmorphogenic concentration of cyclopamine was determined in vitro via mouse whole-embryo culture assays to be 2.0 mu M. We administered cyclopamine to female C57BL/6J mice at varied doses by oral gavage, ip injection, or osmotic pump infusion and assessed toxicity and pharmacokinetic (PK) models. Bolus administration was limited by toxicity and rapid clearance. In vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum steady-state concentration of similar to 2 mu M with a corresponding amniotic fluid concentration of approximately 1.5 mu M. Gross facial defects were induced in 30% of cyclopamine-exposed litters, with affected embryos exhibiting cleft lip and palate. This is the first report describing the PKs and teratogenic potential of cyclopamine in the mouse and demonstrates that transient Hh signaling inhibition induces facial clefting anomalies in the mouse that mimic common human birth defects.