The overall goal of this research program is to establish the relationship between expression of xenobiotic metabolizing enzymes, xenobiotic metabolism, and neurotoxicity. The neurotoxicity of many xenobiotics is characterized by remarkably specific involvement of particular cell types (pathoclisis) which may reflect unique differences in xenobiotic metabolism in targeted cells. The hypothesis of the proposed research is that regulation of expression of phase I and phase II enzymes in the nervous system is cell specific and this heterogeneity forms the basis for selective vulnerability of cells to some neurotoxicants. Preliminary data using immunocytochemistry and RT-PCR analysis show that CYP2E1, and class alpha, mu, and pi glutathione S-transferase (GST) expression is cell- specific in neural tissues. The proposed experiments will focus on the cerebellum and dorsal root ganglia (DRG) since certain cell types in these tissues exhibit selective vulnerability to experimental and therapeutic neurotoxicants. Gender and species differences in susceptibility to neurotoxicants will be exploited to determine relative contributions of the metabolic enzymes to neurotoxic outcome. Since little information is presently available regarding distribution of drug metabolizing enzymes in the nervous system, systematic characterization of the distribution of the enzymes and their responses to known inducers is required prior to testing the hypothesis using selected neurotoxic agents. Thus, the specific objectives of this research are addressed by the following questions: 1. Are there cell-specific patterns in the distribution of the xenobiotic metabolizing enzymes in cerebellum and DRG (which predispose discrete cellular populations to neurotoxicity)? 2. Are drug metabolizing enzymes in the brain inducible by xenobiotics and if so, is the induction cell-specific? 3. Does the cellular distribution of xenobiotic metabolizing enzymes determine and influence the cells response to neurotoxic chemicals? The relationships will be examined in two pathoclitic models of neurotoxicity; a. Acrylamide neurotoxicity in cerebellum and DRG. b. Methyl chloride neurotoxicity to cerebellar granule cells. These objectives will be approached using a variety of contemporary methodologies capable of detecting the distribution and expression of phase I and II enzymes in vivo and in vitro. The data resulting from these studies will provide a foundation for future mechanistic studies in which manipulation of enzyme level or activity, alone or in combination with other approaches, may be employed to determine the basis of neurotoxicity.
| Morse, D C; Stein, A P; Thomas, P E et al. (1998) Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain. Toxicol Appl Pharmacol 152:232-9 |
