Substrates for neural metabolism of xenobiotics in adult and developing brain

Cellular heterogeneity and structural complexity of the nervous system, coupled with regional and cellular differences in the metabolic capabilities of neurons, glia and other non-neuronal elements, may underlie the selective cellular involvement following exposure to neurotoxicants. Determination of the role of biotransformation of xenobiotics in neural pathoclisis requires an understanding of the cellular distribution of both phase I and phase II enzyme systems in the brain. While ependyma, choroid plexus and endothelial linings of blood vessels throughout the nervous system appear to contain appreciable amounts of several isoforms of cytochrome P450 (CYP450), glia and neurons tend to be highly specific in which forms of CYP450 they express. Regional and cellular heterogeneity similarly characterize the distribution of glutathione (GSH) and the conjugating enzyme glutathione S-transferase (GST) in the brain. While all cells of the embryonic nervous system express high levels of GSH and pi-GST (with lesser amounts of alpha- and mu-class), by adulthood neurons and non-neuronal cells differ in the distribution of GSH and isoforms of GST. Neurons (except the dorsal root ganglia and the cerebellar granule cells) become GSH-negative but contain alpha-, mu-, and pi-GST. Glia, ependyma, choroid plexus and neurovascular cells are rich in GSH and variously express GSTs. The differences found in the cellular distribution of GSH and GSTs may contribute to changes in the vulnerability of the nervous system to neurotoxicants at different ages. A comprehensive understanding of the neurotoxicological and pharmacological consequences of the cellular heterogeneity in the localization the CYP450s and glutathione S-transferases pre- and postnatally will require systematic study of the distribution, substrate specificity, and inducibility of the various isoforms of these enzyme systems.