DRUG-METABOLISM IN IN-VITRO ORGANOTYPIC AND CELLULAR-MODELS OF MAMMALIAN CENTRAL-NERVOUS-SYSTEM - ACTIVITIES OF MEMBRANE-BOUND EPOXIDE HYDROLASE AND NADPH-CYTOCHROME P-450 (C) REDUCTASE

The membrane-bound form of epoxide hydrolase and NADPH-cytochrome P-45 0 (c) reductase are two important enzymes involved in the bioactivatio n/bioinactivation balance of cerebral tissue. In vivo, the development al profiles and regional localizations of these two enzymes were inves tigated in the rat. The regional distribution study showed that they a re ubiquitously present among the major brain structures. Both enzyme activities were present in the brain prior to birth, and hence tissue from early developmental stages is suitable to develop in vitro cellul ar or organotypic models for toxicity studies involving these metaboli c pathways. Because various neurotoxicological effects can be dependen t on spatio-temporally regulated cell-cell interactions, we aimed to e mploy organotypic tissue cultures in which the cytoarchitecture was we ll preserved. In such cultures, the temporal expression profiles of ep oxide hydrolase and NADPH cytochrome(c) P-450 reductase reflected the in vivo situation. The technically less demanding pure neuronal and gl ial cell cultures were also investigated. Detoxification of benzopyren e-4, 5-epoxide and superoxide production arising from the reductive me tabolism of various drugs were determined in all three systems. The re sults indicate that though organotypic culture is a good model for the metabolic pathways studied, less complicated single cell cultures can also represent appropriate model systems, providing that the expressi on of the enzymes involved has been first established in these systems . NADPH-cytochrome P-450 reductase-dependent metabolism is active in b oth neuronal and glial cells, whereas the detoxification of reactive e poxides occurs mainly in glia. (C) 1998 Intox Press, Inc.