Atropselective Partitioning of Polychlorinated Biphenyls in a HepG2 Cell Culture System: Experimental and Modeling Results

Cell culture models are used to study
the toxicity of polychlorinated
biphenyls (PCBs); however, it is typically unknown how much PCB enters
the cells and, for chiral PCBs, if the partitioning is atropselective.
We investigated the partitioning of racemic PCB 91, PCB 95, PCB 132,
and PCB 136 in HepG2 cells following a 72 h incubation. PCBs were
present in the cell culture medium (60.7–88.8%), cells (8.0–14.6%),
and dishes (2.3–7.8%) and displayed atropisomeric enrichment
in the cells (enantiomeric fraction [EF] = 0.55–0.77) and dishes
(EF = 0.53–0.68). Polyparameter linear free energy relationships
coupled with a composition-based model provided a good estimate of
the PCB levels in the cells and cell culture medium. The free concentration
was subsequently used to extrapolate from the nominal cell culture
concentration to PCB tissue levels and vice versa. This approach can be used for in vitro–in vivo extrapolations for all 209 PCB congeners. However, this model (and
modified models based on descriptors incorporating atropselective
interactions, i.e., relative retention times on chiral columns) did
not predict the atropselective partitioning in the cell culture system.
Improved chemical descriptors that account for the atropselective
binding of PCBs to biological macromolecules are, therefore, needed
to predict the atropselective partitioning of PCBs in biological systems.

细胞培养模型（cell culture models）常被用于研究多氯联苯（polychlorinated biphenyls, PCBs）的毒性，但目前通常无法明确有多少多氯联苯会进入细胞，且对于手性多氯联苯而言，其分配过程是否具有阻转选择性（atropselective）也尚不明确。
本研究针对外消旋PCB 91、PCB 95、PCB 132及PCB 136在孵育72小时后于HepG2细胞中的分配情况展开了探究。结果显示，多氯联苯主要分布于细胞培养液中（占比60.7%~88.8%），其次为细胞内（8.0%~14.6%），以及培养皿表面（2.3%~7.8%）；且在细胞内（对映体分数[EF]=0.55~0.77）与培养皿表面（EF=0.53~0.68）均观察到阻转异构体富集现象。
将多参数线性自由能关系（polyparameter linear free energy relationships）与基于组分的模型（composition-based model）相结合，可较好地估算细胞内与细胞培养液中的多氯联苯含量。随后，研究人员利用游离浓度（free concentration），实现了从名义细胞培养液浓度（nominal cell culture concentration）到多氯联苯组织浓度的外推，反之亦然。该方法可用于全部209种多氯联苯同系物的体外-体内外推（in vitro–in vivo extrapolations）。
不过，本研究采用的模型（以及基于纳入阻转选择性相互作用描述符的改进模型，即手性色谱柱（chiral columns）相对保留时间相关描述符）无法预测该细胞培养体系中的阻转选择性分配过程。因此，亟需开发可表征多氯联苯与生物大分子（biological macromolecules）阻转选择性结合的新型化学描述符（chemical descriptors），以准确预测多氯联苯在生物体系中的阻转选择性分配行为。