A CELL-CULTURE ANALOG OF RODENT PHYSIOLOGY - APPLICATION TO NAPHTHALENE TOXICOLOGY

The difficulties of large-scale animal testing of compounds has spurred development of in vitro testing methods and physiologically based pharmacokinetic models (PBPK). In existing in vitro methods, tissue interactions occurring in vivo are not reproduced accurately and in PBPKs the a priori prediction of metabolism is difficult. Through development of a multicompartmental, multiple cell type bioreactor system these limitations can be circumvented. A cell culture analogue (CCA) of a PBPK was developed. The CCA contains multiple chambers, each of which represents a tissue or group of similar tissues as specified in the PBPK. Proof-of-concept experiments were done using naphthalene as a model. Naphthalene is converted into naphthalene oxide and the circulation of this reactive metabolite from the liver to lung is a possible mechanism for lung injury. A CCA with liver, lung and other tissue compartments was constructed. This system was used in conjunction with cultured H4IIE rat hepatoma cells and L2 rat lung cells to study the importance of circulated naphthalene metabolites (presumably naphthalene oxides) on lung cell toxicity in rodents. By increasing the number of cells and/or inducing cytochrome P-450 activity in the liver compartment, lung cell mortality was increased. Glutathione depletion in the lung and liver cells was also observed. These results indicate that the CCA is a potentially useful concept for studying the action of compounds with reactive metabolites.