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

The difficulties of large-scale animal testing of compounds has spurre d development of in vitro testing methods and physiologically based ph armacokinetic models (PBPK). In existing in vitro methods, tissue inte ractions occurring in vivo are not reproduced accurately and in PBPKs the a priori prediction of metabolism is difficult. Through developmen t of a multicompartmental, multiple cell type bioreactor system these limitations can be circumvented. A cell culture analogue (CCA) of a PB PK was developed. The CCA contains multiple chambers, each of which re presents 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 o f this reactive metabolite from the liver to lung is a possible mechan ism for lung injury. A CCA with liver, lung and other tissue compartme nts was constructed. This system was used in conjunction with cultured H4IIE rat hepatoma cells and L2 rat lung cells to study the importanc e 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, lu ng 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 wit h reactive metabolites.