Kohn M C, Sewall C H, Lucier G W, Portier C J
Laboratory of Quantitative and Computational Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1996 Jan;136(1):29-48. doi: 10.1006/taap.1996.0004.
A physiological dosimetric model of the disposition of TCDD in the rat (Kohn et al., Toxicol. Appl. Pharmacol. 120, 138-154, 1993) was extended to include effects of dioxin on serum concentrations of thyroid hormones in the rat. The extended model included distribution of blood among major vessels and tissue capillary beds and resorption of TCDD released into the gut lumen from the liver by cell lysis consequent to cytotoxicity. TCDD metabolism was represented by Hill kinetics. Parameter values were estimated by fitting time-course data for a single oral subcutaneous injection of TCDD and dose-response data for biweekly oral dosing. The extended model included new compartments for the thyroid and thyroxine-sensitive tissues (e.g., pituitary, kidney, and brown fat), secretion and tissue uptake of thyroid hormones, binding of 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (thyroxine, T4) to proteins in blood and tissues, deiodination of iodothyronines, and glucuronidation of T4 by the hepatic UDP-glucuronosyltransferase (UGT) activity induced by TCDD. Secretion of thyroid hormones was modeled as regulated by thyrotropin (TSH), whose secretion was modeled as regulated by the hypothalamic factors thyrotropin releasing hormone and somatostatin. Release of the hypothalamic factors was modeled as under feedback control by the blood T4 level. Induction of UGT was modeled as stimulated by the Ah receptor-TCDD complex. The extended model fit the observed dose-response of P450 isozymes and Ah and estrogen receptors following repeated oral doses with comparable accuracy as the earlier model. The fit to liver and fat TCDD levels following single and repeated oral and subcutaneous doses was improved over the earlier model. The revised model's predicted liver TCDD concentrations at very low doses were verified experimentally. The model reproduced the responses observed for blood T3, T4, and TSH after 31 weeks of biweekly oral dosing of rats with TCDD. The model also predicted responses of UGT mRNA and UGT enzymatic activity comparable to those observed in TCDD-treated rats in experiments whose data were not used in constructing the model. Calculated increases in blood TSH levels are consistent with prolonged stimulation of the thyroid and may represent an early stage in the induction of thyroid tumors identified in previous two-year bioassays. Thus, increases in UGT activity may be useful as a biomarker for tumorigenic changes in hormone levels subsequent to TCDD exposure.
大鼠体内2,3,7,8-四氯二苯并对二噁英（TCDD）处置的生理剂量学模型（Kohn等人，《毒理学与应用药理学》120卷，138 - 154页，1993年）得到扩展，以纳入二噁英对大鼠血清甲状腺激素浓度的影响。扩展后的模型包括主要血管和组织毛细血管床之间的血液分布，以及因细胞毒性导致细胞裂解后从肝脏释放到肠腔中的TCDD的再吸收。TCDD代谢以希尔动力学表示。通过拟合单次口服皮下注射TCDD的时间进程数据和每两周口服给药的剂量反应数据来估计参数值。扩展后的模型包括甲状腺和对甲状腺素敏感组织（如垂体、肾脏和棕色脂肪）的新隔室，甲状腺激素的分泌和组织摄取，3,5,3'-三碘甲腺原氨酸（T3）和3,5,3',5'-四碘甲腺原氨酸（甲状腺素，T4）与血液和组织中蛋白质的结合，碘甲腺原氨酸的脱碘作用，以及由TCDD诱导的肝脏尿苷二磷酸葡萄糖醛酸基转移酶（UGT）活性对T4的葡萄糖醛酸化作用。甲状腺激素的分泌被建模为由促甲状腺激素（TSH）调节，TSH的分泌被建模为由下丘脑因子促甲状腺激素释放激素和生长抑素调节。下丘脑因子的释放被建模为受血液T4水平的反馈控制。UGT的诱导被建模为由芳烃受体 - TCDD复合物刺激。扩展后的模型对多次口服给药后观察到的P450同工酶、芳烃受体和雌激素受体的剂量反应拟合，其准确性与早期模型相当。与早期模型相比，单次和多次口服及皮下给药后对肝脏和脂肪中TCDD水平的拟合有所改善。在极低剂量下，经实验验证了修订模型预测的肝脏TCDD浓度。该模型再现了大鼠每两周口服TCDD 31周后血液中T3、T4和TSH的反应。该模型还预测了UGT mRNA和UGT酶活性的反应，与在构建模型时未使用其数据的实验中TCDD处理大鼠中观察到的反应相当。计算得出的血液TSH水平升高与甲状腺的长期刺激一致，可能代表了在先前两年生物测定中确定的甲状腺肿瘤诱导的早期阶段。因此，UGT活性的增加可能作为TCDD暴露后激素水平致瘤性变化的生物标志物。
