Schisandrin B (Sch B), the most abundant lignan isolated from the fruit of Schisandra chinensis, has been shown to possess a broad spectrum of tissue protection against oxidative injury by enhancing the glutathione antioxidant response, particularly in the heart. Therefore, the elucidation of biochemical mechanism underlying the cardioprotection of Sch B has attracted much interest in the area of preventive medicine. To investigate the role of reactive oxygen species (ROS) arising from cytochrome P450 (CYP)-catalyzed metabolism of (−)Sch B (a more potent stereoisomer of Sch B) in triggering glutathione antioxidant response, (−)Sch B-induced NADPH-dependent and CYP-catalyzed reaction and the associated ROS production were examined in rat heart microsomes. In order to examine the signal t...[ Read more ]

Schisandrin B (Sch B), the most abundant lignan isolated from the fruit of Schisandra chinensis, has been shown to possess a broad spectrum of tissue protection against oxidative injury by enhancing the glutathione antioxidant response, particularly in the heart. Therefore, the elucidation of biochemical mechanism underlying the cardioprotection of Sch B has attracted much interest in the area of preventive medicine. To investigate the role of reactive oxygen species (ROS) arising from cytochrome P450 (CYP)-catalyzed metabolism of (−)Sch B (a more potent stereoisomer of Sch B) in triggering glutathione antioxidant response, (−)Sch B-induced NADPH-dependent and CYP-catalyzed reaction and the associated ROS production were examined in rat heart microsomes. In order to examine the signal transduction pathway involved in the cytoprotective action of Sch B, the effects (−)Sch B on MAPK, PKC and Nrf2 activation, as well as the subsequent eliciting of glutathione antioxidant response and protection against apoptosis were examined in H9c2 cells, a rat cardiomyoblast cell line. Pharmacological tools, such as CYP inhibitor, antioxidants, MAPK inhibitor and Nrf2 RNAi, were also used to delineate the signaling pathway. The results indicated that Sch B induced ROS production, presumably by the CYP-catalyzed reaction, in H9c2 cells and rat heart microsomes. The ROS production seemed to cause the activation of MAPK in H9c2 cells, with the degree of ERK activation being much larger than that of p38 or JNK. The MAPK activation was followed by an increase in the level of nuclear Nrf2, an indirect measure of Nrf2 activation, and the eliciting of a glutathione antioxidant response. Consistently, the enhancements of cellular/mitochondrial glutathione antioxidant status by Sch B pre-treatment may be causally associated with cyto/cardioprotection against different oxidative stress-induced injuries caused by menadione, hypoxia/reoxygenation, tert-butyl hydroperoxide and ischemia/reperfusion. Besides, the increased resistance of cardiomyocytes to counteract oxidative stress might be partially due to the augmentation of GSH recovery capacity, which was mainly mediated the stimulation of the glutathione redox cycling. Moreover, results obtained from comparative studies on Sch B analogs and other dietary phytochemicals also support the role of ROS in eliciting the glutathione antioxidant response. In conclusion, experimental results strongly support the hypothesis that a threshold amount of ROS arising from the CYP-catalyzed metabolism of Sch B trigger a redox-sensitive ERK/Nrf2 signaling, which then elicit glutathione antioxidant response and cause cardioprotection in vitro and ex vivo.