Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation
Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation
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DOI：
10.1006/taap.1996.8067
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发表时间：
1997-05-01
影响因子：
3.8
通讯作者：
Eklund, CR
中科院分区：
文献类型：
--
作者：
Andersen, ME;Birnbaum, LS;Eklund, CR
将2，3，7，8-四氯二苯并-对-二恶英（TCDD）的生理药代动力学（PBPK）模型与肝脏分区的五室几何模型相结合，预测肝脏内CYP 450蛋白的总诱导和局部诱导。分析了三篇关于TCDD在雌性大鼠体内的药代动力学和蛋白诱导的文献研究。在模拟低剂量行为的mRNA在整个肝脏，特别是在代表免疫组化观察，五室模型是更成功的比传统的均匀的一室肝脏模型，五室肝脏模型中使用的亲和力TCDD的Ah受体（AhR）保持恒定的所有肝脏（K-b = 0.2 nM）。AhR-TCDD复合物对CYP 1A 1（K-d1）和CYP 1A 2（K-d2）基因中TCDD反应元件的推定亲和力在相邻隔室之间变化为3倍，该参数化导致预测小叶中心和门静脉周围区域之间的亲和力差异为81倍。在三项模拟研究中，用于AhR-TCDD复合物与隔室3（中间区）中CYP 1A 2的TCDD响应元件结合的亲和力范围为0.08至1.0 nM。对于CYP 1A 1，隔室3中的相应解离常数在0.6至2.0 nM之间变化。在每个隔室中，诱导的Hill系数必须为4或更大，以匹配免疫组织化学结果。该多室肝脏模型与整个肝脏的蛋白质和mRNA诱导以及这些蛋白质的区域分布的数据一致，以前的模型没有纳入诱导的区域变化，基于多室肝脏模型的PBPK分析表明，TCDD对肝脏CYP 1A 1/CYP 1A 2诱导的低剂量行为是高度非线性的。(C)1997年学术出版社。
A physiologically based pharmacokinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was combined with a five-compartment geometric model of hepatic zonation to predict both total and regional induction of CYP450 proteins within the liver. Three literature studies on TCDD pharmacokinetics and protein induction in female rats were analyzed. In simulating low-dose behavior for mRNA in whole liver and, particularly, in representing immunohistochemical observations, the five-compartment model was more successful than conventional homogeneous one-compartment liver models, The five-compartment liver model was used with the affinity of TCDD for the Ah receptor (AhR) held constant across all the liver (K-b = 0.2 nM). The presumed affinities of the AhR-TCDD complex for TCDD responsive elements in the CYP1A1 (K-d1) and CYP1A2 (K-d2) genes varied between adjacent compartments by a factor of 3, This parameterization leads to predicted 81-fold differences in affinities between the centrilobular and the periportal regions. The affinities used for AhR-TCDD complex binding to TCDD response elements for CYP1A2 in compartment 3 (the midzonal area) ranged from 0.08 to 1.0 nM in the three studies modeled. For CYP1A1 the corresponding dissociation constant in compartment 3 varied from 0.6 to 2.0 nM. In each compartment, the Hill coefficient for induction had to be 4 or greater to match the immunohistochemical results. This multicompartment liver model is consistent with data on protein and mRNA induction throughout the liver and on the regional distribution of these proteins, No previous model has incorporated regional variations in induction, The PBPK analysis based on the multicompartment liver model suggests that the low-dose behavior for hepatic CYP1A1/CYP1A2 induction by TCDD is highly nonlinear. (C) 1997 Academic Press.