Fay Kellie A, Fitzsimmons Patrick N, Hoffman Alex D, Nichols John W
National Health and Environmental Effects Research Laboratory, Office of Research and Development, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA.
Environ Toxicol Chem. 2017 Feb;36(2):463-471. doi: 10.1002/etc.3572. Epub 2016 Aug 25.
Isolated hepatocytes and liver S9 fractions have been used to collect in vitro biotransformation data for fish as a means of improving modeled estimates of chemical bioaccumulation. To date, however, there have been few direct comparisons of these 2 methods. In the present study, cryopreserved trout hepatocytes were used to measure in vitro intrinsic clearance rates for 6 polycyclic aromatic hydrocarbons (PAHs). These rates were extrapolated to estimates of in vivo intrinsic clearance and used as inputs to a well stirred liver model to predict hepatic clearance. Predicted rates of hepatic clearance were then evaluated by comparison with measured rates determined previously using isolated perfused livers. Hepatic clearance rates predicted using hepatocytes were in good agreement with measured values (<2.1-fold difference for 5 of 6 compounds) under 2 competing binding assumptions. These findings, which may be attributed in part to high rates of PAH metabolism, are similar to those obtained previously using data from liver S9 fractions. For 1 compound (benzo[a]pyrene), the in vivo intrinsic clearance rate calculated using S9 data was 10-fold higher than that determined using hepatocytes, possibly due to a diffusion limitation on cellular uptake. Generally, however, there was good agreement between calculated in vivo intrinsic clearance rates obtained using either in vitro test system. These results suggest that both systems can be used to improve bioaccumulation assessments for fish, particularly when vitro rates of activity are relatively high, although additional work is needed to determine if the chemical domain of applicability for each system differs. Environ Toxicol Chem 2017;36:463-471. Published 2016 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
分离的肝细胞和肝脏S9组分已被用于收集鱼类的体外生物转化数据，作为改进化学物质生物累积模型估计的一种手段。然而，迄今为止，这两种方法之间几乎没有直接比较。在本研究中，使用冷冻保存的鳟鱼肝细胞来测量6种多环芳烃（PAH）的体外固有清除率。这些速率被外推以估计体内固有清除率，并用作输入到充分搅拌的肝脏模型中以预测肝脏清除率。然后通过与先前使用离体灌注肝脏测定的测量速率进行比较，来评估预测的肝脏清除率。在两种竞争性结合假设下，使用肝细胞预测的肝脏清除率与测量值高度一致（6种化合物中有5种的差异<2.1倍）。这些发现部分可能归因于PAH的高代谢率，与先前使用肝脏S9组分数据获得的结果相似。对于1种化合物（苯并[a]芘），使用S9数据计算的体内固有清除率比使用肝细胞测定的清除率高10倍，这可能是由于细胞摄取存在扩散限制。然而，一般来说，使用任一体外测试系统计算的体内固有清除率之间具有良好的一致性。这些结果表明，这两种系统均可用于改进鱼类的生物累积评估，特别是当体外活性速率相对较高时，尽管还需要进一步的工作来确定每个系统的化学适用范围是否不同。《环境毒理学与化学》2017年；36：463 - 471。2016年由SETAC出版。本文是美国政府的作品，因此在美国属于公共领域。
