Figure 10.1:Inhibition of LSE on the Elevation of sALT and sAST Level Produced by 160mg/kg APAP. Mean ± SD for eight mice. ^*p<0.05 , ^**p<0.01 vs normal group; P<0.05, p<0.01 vs APAP group.

Preventive Effect of LSE Against APAP-induced Liver Histopathological Changes

Histopathological changes occurred in the APAP treatment group (Figure 10.3B). Hepatocytes around the central veins were eosinophilic in appearance particularly, and showed cytoplasmic vacuolization with the presence of necrotic areas in the centrilobular regions. When 100 mg/kg LSE was given to mice prior to the APAP treatment (Figure 10.3C), the liver damage was reduced to some extent with less eosinophilia, but there were still swollen hepatocytes surrounding the central veins. With 200 mg/kg LSE and 400 mg/kg (Figures 10.3D and 10.3E), the area of liver damage was further reduced.

Figure 10.2: Protective Effect of LSE on APAP-Induced Decrease of Serum GSH Content. Mean ± SD for eight mice. *P<0.05 vs. normal group; #P<0.05 vs. APAP group.

Reversed Ca²⁺-induced Mitochondrial Swelling Ability Following the Treatment of LSE

As shown in Figure 10.4, 100 µM Ca²⁺ induced the swelling of normal liver mitochondria, which was greatly attenuated in mice with pretreatment of 160 mg/kg APAP. LSE at a dose of 100 mg/kg blocked the attenuation induced by APAP to some extent, and the inhibitive rate was about–18.8 per cent, while at the doses of 200 mg/kg and 400 mg/kg, the inhibitive rates were up to –67.2 per cent and –72.7 per cent, respectively.

Protective Effect of LSE Against APAP-Induced Dissipation of MMP

Compared with the MMP of normal mice (–172.6±13.6 mV), MMP in APAP treatment group was decreased to –114.2±10.3 mV (Figure 10.5), which was reverted to–132.9±6.3 mV, –138.2±12.4 mV and –154.9±12.8 mV, respectively, following preadministration of LSE at doses of 100, 200 and 400 mg/kg. Although it seemed difficult to entirely recuperate the dissipation of MMP induced by APAP, the restoring trend was definite.

Figure 10.3:Effects of LSE Pretreatment on APAP-Induced Liver Damage in Mice

(A) Liver from mice in normal group; (B) liver from mice treated with APAP; (C–E) liver from mice treated with APAP plus 100•C200 or 400 mg/kg LSE respectively.

Effect of LSE on the Transcription of Liver VDAC Gene

To assess the transcription of VDAC, RT-PCR was performed using total RNA isolated from mice liver homogenates. As shown in Figure 6, the VDAC mRNA level in the liver homogenates of APAP treatment group was significantly elevated, against that of normal group. However, the expression of VDAC was down-regulated when mice were pretreated with 100 mg/kg, 200 mg/kg and 400 mg/kg LSE.

Discussion

In the present study, we used APAP, a widely used analgesic and antipyretic, to make the liver injury model(Mitchell et al.,1973). Mitochondrial dysfunction plays an important role in the mechanisms of APAP hepatotoxicity. N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of APAP by the P450 system, depletes GSH in vivo and covalently binds to cellular proteins causing functional deficits within the cell(Jaeschke et al.,2006; Mitchell et al.,

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