||(-)Schisandrin B [(-)Sch B], a stereoisomer of schisandrin B (Sch B), is a dibenzocyclooctadiene derivative isolated from Fructus Schisandrae. To elucidate the signal transduction pathway triggered by (-)Sch B, the effects of (-)Sch B on cytochrome P-450 (CYP)-mediated reactive oxygen species (ROS) production, activations of mitogen-activated protein kinases, nuclear factor erythroid 2-related factor 2 (Nrf2) , and the subsequent induction of glutathione antioxidant response and cytoprotection against apoptosis in AML12 cells were examined. Whether or not Sch B analogs and prooxidants can elicit a protective glutathione antioxidant response against oxidant-induced injury in vitro and in vivo was investigated. Results indicated that ROS arising from the CYP-catalyzed metabolism of (-)Sch B triggers a redox-sensitive extracellular signal-regulated kinase (ERK)/Nrf2 signal transduction pathway, which then induces a cellular/hepatic glutathione antioxidant response and protects against oxidant-induced injury in AML12 cells. The cytoprotective effect afforded by (-)Sch B is causally related to its ability in enhancing reduced glutathione recovery capacity. Results obtained from comparative studies among Sch B and its analogs supported the involvement of ROS-mediated reaction in the cyto/hepatoprotection afforded by schisandrins. Findings from comparative studies among Sch B and other prooxidants support the postulation that prooxidants can invariably induce the glutathione antioxidant response and confer cytoprotection against oxidant injury in vitro. Whether or not the prooxidant of interest can produce a similar response in vivo would depend on the bioavailability of the compound via oral route and the potential toxic effect of its prooxidant action. In this regard, Sch B seems to be a more promising candidate in conferring hepatoprotection than that of other prooxidants, as it has a relatively high bioavailability and seemingly low toxicity in vivo. Future studies should be focused on the clinical usage of Sch B in the treatment of oxidative stress-related liver diseases.