Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies

摘要

Deficiencies in the early ADMET (absorption, distribution, metabolism, elimination, and toxicity) information on drug candidates extract a significant economic penalty on pharmaceutical firms. We have developed a microscale cell culture analog (muCCA) device that can potentially provide better, faster, and more efficient prediction of human and animal responses to a wide range of chemicals. The system described in this paper is a simple four-chamber muCCA ("lung"-"liver"-"fat"-"other tissue") designed on the basis of a physiologically based pharmacokinetics (PBPK) model of a rat. Cultures of L2, HepG2/C3A, and differentiated 3T3-L1 adipocytes were selected to mimic the key functions of the lung, liver, and fat compartments, respectively. Here, we have demonstrated the application of the muCCA system to study bioaccumulation, distribution, and toxicity of selected compounds. Results from the bioaccumulation study reveal that hydrophobic compounds such as fluoranthene preferentially accumulated in the fat chamber. Only a small amount of fluoranthene was observed in the liver and lung chambers. In addition, the presence of the differentiated 3T3-L1 adipocytes in the muCCA device significantly reduced naphthalene and naphthoquinone-induced glutathione (GSH) depletion. These findings suggest the potential utilization of the muCCA system to assess ADMET characteristics of the compound of interest prior to animal or human trials.