Unité METO, INERIS, Parc Technologique Alata, BP 2, 60550, Verneuil-en-Halatte, France.
Toxicol Lett. 2011 Sep 10;205(3):310-9. doi: 10.1016/j.toxlet.2011.06.021. Epub 2011 Jun 23.
Recently, physiologically based perfusion in vitro systems have been developed to provide cell culture environment close to in vivo cell environment (e.g., fluidic conditions, organ interactions). In this work, we model and compare the fate of a chemical, benzo[a]pyrene (B[a]P), in a perfusion and a standard (static well-plate) system. These in vitro systems are composed of Caco-2 and HepG2 cells so as to mimic absorption across the small intestine and intestinal and hepatic metabolism. Compartmental models were developed and calibrated with B[a]P kinetics data in the culture medium to estimate the apparent permeability of Caco-2 cells, the in vitro biotransformation of B[a]P, as well as the different routes of loss by non-specific adsorption. Our results show that non-specific binding is the main process responsible for the depletion of B[a]P in the culture media: at steady state, only 40% and 24% of the total concentration of B[a]P are bioavailable in the static and perfused systems, respectively. We also showed that Caco-2 permeability in the perfused culture system is closer to in vivo conditions than the one obtained in the static system and that higher cellular metabolic activities are observed in static conditions. Perfused in vitro systems combined with kinetic modelling are promising tools for studying in vitro the different processes involved in the toxicokinetics of xenobiotics.
最近，已经开发出基于生理学的体外灌注系统，以提供更接近体内细胞环境的细胞培养环境（例如，流体条件、器官相互作用）。在这项工作中，我们对一种化学物质苯并[a]芘（B[a]P）在灌注和标准（静态微孔板）系统中的命运进行建模和比较。这些体外系统由 Caco-2 和 HepG2 细胞组成，以模拟小肠吸收和肠内和肝内代谢。建立了房室模型，并使用培养基中 B[a]P 的动力学数据进行了校准，以估计 Caco-2 细胞的表观渗透率、B[a]P 的体外生物转化以及通过非特异性吸附的不同损失途径。我们的结果表明，非特异性结合是导致培养基中 B[a]P 耗尽的主要过程：在稳态时，B[a]P 的总浓度只有 40%和 24%分别在静态和灌注系统中具有生物利用度。我们还表明，灌注培养系统中的 Caco-2 渗透率比静态系统更接近体内条件，并且在静态条件下观察到更高的细胞代谢活性。结合动力学模型的灌注体外系统是研究外源性化学物质毒代动力学中涉及的不同过程的有前途的工具。
