Han Xing, Nabb Diane L, Mingoia Robert T, Yang Ching-Hui
DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware 19714, USA.
Environ Sci Technol. 2007 May 1;41(9):3269-76. doi: 10.1021/es0626279.
Bioaccumulation in fish depends on the dynamics of various processes that involve fish uptake, storage, and elimination of xenobiotics. Elimination via fish biotransformation is a primary process that can be evaluated in an in vitro system to improve the performance of the prediction of xenobiotic bioaccumulation potentials. In this study, values of intrinsic clearance (CLint) of seven reference compounds (atrazine, molinate, 4,4-bis(dimethylamino)-benzophenone, 4-nonylphenol, 2,4-di-tert-butylphenol, trifluralin, benzo(a)pyrene) in hepatocytes freshly isolated from rainbow trout and rat were determined using a substrate depletion approach. Atrazine was metabolized in rat hepatocytes with a CLint value of 3.81 +/- 1.96 mL/h/ 10(6) cells, whereas in trout hepatocytes, the clearance was not significant until very high cell concentration was used and the rate was estimated to be approximately 0.002 mL/h/10(6) cells. Intrinsic clearance values for all other compounds were 5.5-78.5-fold lower in trout hepatocytes than those in rat hepatocytes. Trout hepatic clearance (CL(H)) values were extrapolated from the CLint values using a "well-stirred" liver model. Biotransformation rate constants (kMET) of the compounds in trout were subsequently estimated and used as inputs to a kinetic model for the prediction of bioconcentration factors (BCF) in fish. Compared to the BCF values predicted without consideration of fish biotransformation, the inclusion of estimated kMET values significantly improved fish BCF predictions for the reference compounds. This study demonstrates a framework for future bioaccumulation assessment of xenobiotics using combined information of the physical-chemical properties of the compounds and the biotransformation potentials of the compounds in fish.
鱼类中的生物累积取决于各种过程的动态变化，这些过程涉及鱼类对异生素的摄取、储存和消除。通过鱼类生物转化进行消除是一个主要过程，可以在体外系统中进行评估，以提高对异生素生物累积潜力预测的性能。在本研究中，使用底物消耗法测定了从虹鳟鱼和大鼠新鲜分离的肝细胞中七种参考化合物（阿特拉津、禾草敌、4,4-双（二甲基氨基）-二苯甲酮、4-壬基酚、2,4-二叔丁基酚、氟乐灵、苯并[a]芘）的内在清除率（CLint）值。阿特拉津在大鼠肝细胞中代谢，CLint值为3.81±1.96 mL/h/10(6)个细胞，而在鳟鱼肝细胞中，直到使用非常高的细胞浓度时清除率才显著，估计速率约为0.002 mL/h/10(6)个细胞。鳟鱼肝细胞中所有其他化合物的内在清除率值比大鼠肝细胞中的低5.5-78.5倍。使用“充分搅拌”的肝脏模型从CLint值推断出鳟鱼肝脏清除率（CL(H)）值。随后估计了这些化合物在鳟鱼中的生物转化率常数（kMET），并将其用作动力学模型的输入，以预测鱼类中的生物浓缩因子（BCF）。与不考虑鱼类生物转化预测的BCF值相比，纳入估计的kMET值显著改善了参考化合物的鱼类BCF预测。本研究展示了一个框架，用于未来利用化合物的物理化学性质和化合物在鱼类中的生物转化潜力的综合信息对异生素进行生物累积评估。
