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. 2008 Sep;13(3):347-55.
doi: 10.1007/s12192-008-0034-4. Epub 2008 Apr 8.

Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice

Xiu Qi Bao  1 , Geng Tao Liu
Affiliations

Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice

Xiu Qi Bao et al. Cell Stress Chaperones. 2008 Sep.

Abstract

Heat shock proteins (HSPs) are the best-known endogenous factors that protect against cell injury under various pathological conditions and that can be induced by various physical, chemical, and biological stressors. New research seeks to discover a compound that is clinically safe and can induce the accumulation of HSPs in patients. This paper reports that the oral administration of three doses of bicyclol, a novel antihepatitis drug, induced hepatic HSP27 and HSP70 expression in a time- and dose-dependent manner, and that bicyclol treatment stimulated heat shock factor 1 (HSF1) activation in mice. The inducing effects of bicyclol on HSP27, HSP70 and HSF1 were all blocked by quercetin, an inhibitor of HSP biosynthesis. The cytoprotective effect of HSP27/70 induced by bicyclol against hepatotoxicity of acetaminophen (AP) was assessed in mice. The prior administration of bicyclol markedly suppressed AP-induced liver injury as indicated by the reduction in the elevation of serum alanine aminotransferase and aspartate aminotransferase, in liver necrosis, in the release of cytochrome c and apoptosis-inducing factor from mitochondria, as well as in hepatic deoxyribonucleic acid fragmentation in mice. However, all the above actions of bicyclol against AP-induced mouse liver injuries were significantly attenuated by quercetin. This is the first report to show that bicyclol induces hepatic HSP27/70 expression via activation of HSF1 and that the cytoprotective action of bicyclol against liver injury is mediated by its induction of HSP27/70. These results provide new evidence for elucidating the mechanism of the hepatoprotective action of bicyclol in animals and patients.

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Figures

Fig. 1
Fig. 1
Time course of bicyclol on the induction of hepatic HSPs in mice. Bicyclol 200 mg/kg was administered orally to mice three times in 24 h as described in the “Materials and methods.” The mice were killed at the indicated times after the last administration. Whole liver proteins from different groups of mice were subjected to Western blot analysis. The inductive action of bicyclol on HSP27/70 was in a time-dependent manner, while bicyclol had no effect on HSP90. Each HSP level was quantified by densitometric analysis. A representative of Western blots from each group is shown. Mean ± SD results of three separate experiments are graphed. Asterisk, number sign, P < 0.05 versus 0 h control mice
Fig. 2
Fig. 2
Dose–effect relationship of bicyclol on hepatic HSP27 and HSP70 expression in mice. a Western blot analysis for HSP27/70 induced by bicyclol 100, 200, and 300 mg/kg administered three times. The inductive action of bicyclol 300 mg/kg was more potent than those of 100 and 200 mg/kg. Mean ± SD results of three to four separate experiments are graphed. Asterisk, number sign, P < 0.05; double asterisk, double number sign, P < 0.01 versus control mice. b Western blot analysis for HSP27/70 induced by three doses and one dose of bicyclol. Densitometric analysis showed that three doses of bicyclol 300 mg/kg induced overexpression of HSP27/70 but that one dose did not. Mean ± SD results of four separate experiments are graphed. Asterisk, P < 0.05; double number sign, P < 0.01 versus control mice
Fig. 3
Fig. 3
Inhibitory effect of quercetin on the inductions of hepatic HSP27 and HSP70 by bicyclol in mice. Quercetin 200 mg/kg was coadministrated with bicyclol 300 mg/kg to mice. The mice were killed 6 h after the last bicyclol administration. Whole liver proteins were extracted for the Western blot assay. A representative Western blot from each group is shown. Mean ± SD results of three separate experiments are graphed. Asterisk, number sign P < 0.05 versus bicyclol (300 mg/kg)-treated mice
Fig. 4
Fig. 4
Effect of bicyclol on the hepatic HSP27 and HSP70 mRNA expression in mice. Mice were administered bicyclol 100, 200, and 300 mg/kg, respectively, for three times in 24 h. Whole liver RNA was extracted for RT-PCR assay (2 μg per lane). The inductive action of bicyclol was in a dose-dependent manner. Mean ± SD results of triplicate experiments are graphed. Asterisk, number sign, P < 0.05; double asterisk, double number sign, P < 0.01 versus control mice, respectively
Fig. 5
Fig. 5
Effect of bicyclol on the activation and nuclear localization of HSF1 in mouse liver. Mice were orally administered bicyclol 100, 200, and 300 mg/kg three times in 24 h. The mice were killed 6 h after the last administration of bicyclol. a Cytosol and nucleus expression of HSF1 and p-HSF1 in mouse liver; a representative of three results is shown. b HSF1-binding activity from whole liver extracts. A representative from three results is shown
Fig. 6
Fig. 6
Effect of bicyclol on the inductions of HSP27 and HSP70 in AP-injected mice. Mice were orally administered bicyclol 300 mg/kg three times in 24 h. They were then subjected to AP 200 mg/kg injection 4 h later and then killed 6 h after the AP injection. Whole liver proteins were extracted for the Western blot assay. A representative Western blot for each group is shown. Mean ± SD results of triplicate experiments are graphed. A representative result is shown. Asterisk, number sign, P < 0.05 versus control mice and AP + bicyclol + quercetin-treated mice; double asterisk, double number sign, P < 0.01 versus control mice and AP + bicyclol + quercetin-treated mice
Fig. 7
Fig. 7
Quercetin attenuated the protective action of bicyclol against liver injury induced by AP in mice. Mice were orally administered bicyclol 300 mg/kg three times in 24 h. They were then subjected to AP 200 mg/kg injection 4 h after the last dosing of bicyclol. Serum and liver tissue were obtained 6 h after AP injection for different determinations. a Liver lesions (hematoxylin–eosin stain, scale bar = 50 μm). b Western blot of cytochrome c and AIF leakage from mitochondia performed from mitochondrial extracts. A representative result is shown. c Representative hepatic DNA fragmentation from each animal of one experiment
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