title: Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies.
abstract: 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 (microCCA) 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 microCCA ("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 microCCA 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 microCCA device significantly reduced naphthalene and naphthoquinone-induced glutathione (GSH) depletion. These findings suggest the potential utilization of the microCCA system to assess ADMET characteristics of the compound of interest prior to animal or human trials.
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14850-5201, USA.
authors.forename: Kwanchanok
authors.initials: K
authors.lastname: Viravaidya
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shuler
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D032701:Biomimetics / Q000295:instrumentation* / Q000379:methods*; D018920:Coculture Techniques / Q000295:instrumentation* / Q000379:methods*; D004341:Drug Evaluation / Q000295:instrumentation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D004867:Equipment Design; D019544:Equipment Failure Analysis; D051379:Mice; D010599:Pharmacokinetics; D051381:Rats; D018675:Toxicity Tests / Q000295:instrumentation* / Q000379:methods*