Hepatoprotective action of schisandrin B against carbon tetrachloride toxicity was mediated by both enhancement of mitochondrial glutathione status and induction of heat shock proteins in mice.
In the present study, we investigated the differential role of the mitochondrial glutathione status and induction of heat shock proteins (HSPs) 25/70 in protecting against carbon tetrachloride (CCl_4) hepatotoxicity in schisandrin B (Sch B)-pretreated mice. The time-course of Sch B-induced changes in these hepatic parameters were examined. Dimethyl diphenyl bicarboxylate (DDB), a non-hepatoprotective analog of Sch B, was studied for comparison. Sch B treatment (2 mmol/kg) produced maximal enhancement in hepatic mitochondrial glutathione status as well as increases in hepatic HSP 25/70 levels at 24 h post-dosing. The stimulatory effect of Sch B then gradually subsided, but the activities of hepatic mitochondrial glutathione reductase (GR) and glutathione S-transferases (GST) as well as the level of HSP 25 remained relatively high even at 72 h post-dosing. CCl_4 challenge caused significant impairment in mitochondrial glutathione status and a decrease in HSP 70 level, but the HSP 25 level was significantly elevated. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl_4 was found to inversely correlate with the time elapsed after the dosing, the protective effect was associated with the ability of Sch B to maintain the mitochondrial glutathione status and/or induce further production of HSP 25 in CCl_4-intoxicated condition. On the other hand, DDB treatment (2 mmol/kg), which did not increase mitochondrial GSH level and GST activity or induce further production of HSP 25 after CCl_4 challenge, could not protect against CCl_4 toxicity. The results suggest that the enhancement of mitochondrial glutathione status and induction of HSP 25/70 may contribute independently to the hepatoprotection afforded by Sch B pretreatment.
Tang
Man Ho
MH
Department of Biochemistry, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong SAR, China.
Chiu
Po Yee
PY
Ko
Kam Ming
KM
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control; D034242:Cyclooctanes / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000378:metabolism; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D034242:Cyclooctanes; D006360:Heat-Shock Proteins; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; D002251:Carbon Tetrachloride; D005978:Glutathione