||Previous studies have demonstrated the hepatoprotective effect of Schisandrin B (Sch B) against carbon tetrachloride (CCl4) toxicity. Recently, many studies have attributed the protective effect of Sch B to its free radical scavenging activity. Preliminary studies in our laboratory showed that the scavenging activity was not sufficient to explain the hepatoprotection produced by Sch B treatment. Therefore, a detailed investigation is necessary in order to define the protective mechanisms of Sch B treatment. Using CCl4-induced toxicity as a model of free radical-mediated hepatocellular damage, our results showed that the hepatoprotection produced by Sch B pretreatment may be due to (1) an increase in reduced glutathione (GSH) levels in hepatic tissue and mitochondria; (2) an increase in hepatic ascorbate concentration; (3) an enhancement in glutathione-S-transferase activity and (4) inhibition of CCl4 metabolism. A comparative study of Sch B with butylated hydroxytoluene, a synthetic phenolic antioxidant, suggested that the increase in hepatic GSH might be a crucial factor in producing the protection. Studies on the hepatoprotective effect of various Schisandrins suggested that both enhancement of hepatic glutathione status and inhibition of CCl4 metabolism were involved in the protective action of Sch B treatment. However, the enhancement of hepatic glutathione status was more important for hepatoprotection. Treating mice with 1,3-bis(2-chloroethyl)- 1 -nitrosourea (BCNU), a specific inhibitor of glutathione reductase, decreased hepatic glutathione reductase activity as well as GSH concentration. However, BCNU treatment could not completely abrogate the hepatoprotective action of Sch B in CCl4-treated mice. A compensatory increase in hepatic ascorbate concentration by BCNU treatment in Sch B-pretreated mice suggested that the hepatoprotective effect of Sch B treatment may be attributed to the enhancement in the functioning of an integrated antioxidant system. This concept was supported by the protection produced by Sch B pretreatment against hepatocellular damage induced by different chemical toxicants.