Protective function of phase II enzymes in chemically-induced oxidative injury to the central nervous system

Oxidative stress resulting from the formation of reactive oxygen species (ROS) from various chemical toxicants and their metabolites, or that arise from endogenous processes is implicated in neuronal toxicity and pathogenesis of prominent neurodegenerative diseases. Many of these chemicals are also substrates for Phase II detoxifying enzymes, including transferases, which possess antioxidant activity. The discovery of an antioxidant response element (ARE) on promoters of these enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), UDP-glucuronosyltansferases (UGTs), and sulfotransferases (SULTs) supports the possibility that Phase II enzymes act collectively to protect the brain from toxic chemicals producing ROS. Expression of these enzymes may be coordinately regulated by signal transduction cascades, including the mitogen activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3-K) pathways, which upon stimulation by a chemical oxidant lead to activation of the ARE and downstream transcription of Phase II genes. Estrogen, a known neuroprotective antioxidant, may induce Phase II enzymes via these signaling cascades. This dissertation reviews work suggesting that Phase II enzymes serve as an important antioxidant defense system in brain and addresses the following specific aims: (A) to test whether NQO1 and SULT1A1, act in concert to reduce chemically-induced oxidative stress by compounds that undergo redox cycling; (B) to determine whether chronic E2-treatment of ACI rats induces Phase II detoxifying enzyme activities in selected brain regions.; Results obtained indicate: (1) SULT1A1 together with NQO1 disrupts redox cycling of menadione, (2) ACI rats respond differently to chronic treatment of estradiol (E2) in a gender and tissue specific manner, (3) chronic E2-treatment induced NQO1, GST, SULT1A1, and UGT activities predominantly in the striata of male ACI rats, but not in females, and (4) amounts of transcription factor Nrf2 correlated inversely with changes in enzyme activities of E2-treated animals. It is concluded that (1) the cooperative action of SULT1A1 and NQO1 in brain prevents the generation of ROS, (2) the neuroprotective effects of E2 are mediated, in part, by the induction of Phase II enzymes, and (3) pathways regulating expression of these enzymes via Nrf2 differ in a gender and tissue specific manner.