The differential role of enhancement in mitochondrial glutathione antioxidant status and induction of heat shock proteins HSP25/70 in the hepatoprotection afforded by schisandrin B (Sch B) against carbon tetrachloride (CCl₄) toxicity was investigated by examining the time-course of these changes in Sch B treated mice in association with the hepatoprotective action. Schisandrin A (Sch A), a structural analog of Sch B, and DDB, a non-hepatoprotective analog, were also studied for comparison. Following the Sch B administration (2 mmol/kg), changes in hepatic mitochondrial glutathione antioxidant status, as assessed by measuring the reduced glutathione (GSH) level and activities of glutathione reductase (GRD), selenium-glutathione peroxidase and glutathione S-transferases (GST), as well as...[ Read more ]

The differential role of enhancement in mitochondrial glutathione antioxidant status and induction of heat shock proteins HSP25/70 in the hepatoprotection afforded by schisandrin B (Sch B) against carbon tetrachloride (CCl₄) toxicity was investigated by examining the time-course of these changes in Sch B treated mice in association with the hepatoprotective action. Schisandrin A (Sch A), a structural analog of Sch B, and DDB, a non-hepatoprotective analog, were also studied for comparison. Following the Sch B administration (2 mmol/kg), changes in hepatic mitochondrial glutathione antioxidant status, as assessed by measuring the reduced glutathione (GSH) level and activities of glutathione reductase (GRD), selenium-glutathione peroxidase and glutathione S-transferases (GST), as well as hepatic HSP25/70 levels were examined at increasing periods (24-72 hr) of post-dosing time. The Sch B pretreated mice were also challenged with CCl₄ (0.1 ml/kg, p.o.) and the extent of hepatocellular damage was assessed by measuring plasma sorbitol dehydrogenase activity and mitochondrial malondialdehyde level at 24 hr post-CCl₄ challenge. The results indicated that Sch B treatment produced time-dependent enhancements in both hepatic mitochondrial glutathione antioxidant status and hepatic HSP25/70 production, with the extent of stimulation being maximum at 24 hr post-dosing. The stimulatory effect then gradually subsided, but the activities of GRD and GST as well as the level of HSP25 remained relatively high even at 72 hr post-dosing. CCl₄ challenge caused significant impairment in mitochondrial glutathione antioxidant status and decrease in HSP7O level, but the HSP25 level was significantly elevated. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl₄ was found to inversely correlate with the time lapsed after dosing, the protective effect was paralleled by the ability of Sch B pretreated animals to maintain mitochondrial glutathione antioxidant status and/or induce a further production of HSP25 or maintain the level of HSP70 under CCl₄ intoxicated condition. Sch A (2 mmo1/kg) treatment, which enhanced hepatic mitochondrial glutathione antioxidant status and HSP25/70 production in control mice at 24 hours post-dosing, could protect against CCl₄ hepatotoxicity. The hepatoprotection was associated with an enhanced mitochondrial glutathione antioxidant status but not HSP25/70 production in CCl₄-intoxicated mice. On the other hand, DDB treatment, which increased HSP25/70 levels but not mitochondrial GSH level and GST activity in control mice, could not protect against CCl₄ toxicity. The ensemble of results suggests that the enhancement of mitochondrial glutathione antioxidant status and induction of HSP25/70, particularly in the face of CCl₄ challenge, may contribute independentIy to the hepatoprotection afforded by Sch B treatment.