Hepatoprotective mechanism of schisandrin B: role of mitochondrial glutathione antioxidant status and heat shock proteins.
In this study, the time course of schisandrin B- (Sch B-) induced changes in hepatic mitochondrial glutathione antioxidant status (mtGAS) and heat shock protein (HSP) 25/70 induction was examined to study their differential roles in the hepatoprotection afforded by Sch B pretreatment against carbon tetrachloride (CCl(4)) toxicity in mice. Dimethyl diphenyl bicarboxylate (DDB), a nonhepatoprotective analog of Sch B, was also included for comparison. The results indicate that Sch B treatment (2 mmol/kg) produced maximum enhancement in hepatic mtGAS and increases in both hepatic HSP 25 and HSP 70 levels at 24 h after dosing. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl(4) was found to correlate inversely with the elapsed time postdosing, the protective effect was associated with the ability to sustain mtGAS and/or HSP 70 levels in a CCl(4)-intoxicated condition. On the other hand, DDB (2 mmol/kg) treatment, which did not sustain mtGAS and HSP 70 level, could not protect against CCl(4) toxicity. Abolition of the Sch B-mediated enhancement of mtGAS by buthionine sulfoximine/phorone did not completely abrogate the hepatoprotective action of Sch B. The results indicate that Sch B pretreatment independently enhances mtGAS and induces HSP 25/70 production, particularly under conditions of oxidative stress, thereby protecting against CCl(4) hepatotoxicity.
Chiu
Po Yee
PY
Department of Biochemistry, The Hong Kong University of Science and Technology, Hong Kong, China.
Tang
Man Ho
MH
Mak
Duncan H F
DH
Poon
Michel K T
MK
Ko
Kam Ming
KM
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000494:pharmacology; D034242:Cyclooctanes / Q000494:pharmacology*; D004149:Dioxoles / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011083:Polycyclic Compounds / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D034242:Cyclooctanes; D004149:Dioxoles; D004791:Enzyme Inhibitors; D005609:Free Radicals; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D017705:Lignans; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011083:Polycyclic Compounds; C015499:schizandrin B; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D005978:Glutathione