Abstract
Bicyclol [4,4′-dimethoxy-5,6,5′,6′-bis(methylenedioxy)-2-hydroxy-methyl-2′-methoxycarbonyl biphenyl] is a synthetic hepatoprotectant widely used in clinical practice, but resistance to this treatment is often observed. We found that the hepatoprotective effect of bicyclol was greatly compromised in female and castrated male mice. This study was to dissect the molecular basis behind the sex difference, which might underlie the clinical uncertainty. We compared bicyclol-induced hepatoprotection between male and female mice using acute liver damage models. Inducible knockout by the Cre/loxp system was used to decipher the role of heat shock transcription factor 1 (HSF1). Functional experiments, western blot, and histopathological analysis were used to determine the key causative factors which might antagonize bicyclol in female livers. HSF1 activation and heat shock protein 70 (Hsp70) expression, which were responsible for bicyclol-induced hepatoprotection, were compromised in female and castrated male livers. Compromised HSF1 activation was a result of HSF1 phosphorylation at serine 303, which was catalyzed by glycogen synthase kinase 3β (GSK3β). Testosterone was necessary for bicyclol to inhibit hepatic GSK3β activity. Administration of testosterone or GSK3β inhibitors restored bicyclol-induced protection in females. Bicyclol induces sex-specific hepatoprotection based on a sex-specific HSF1/Hsp70 response, in which testosterone and GSK3β play key roles. Because a lot of patients suffering from liver diseases have very low testosterone levels, our results give a possible explanation for the clinical variation in bicyclol-induced hepatoprotection, as well as practicable solutions to improve the effect of bicyclol.
Footnotes
- Received December 24, 2014.
- Accepted April 21, 2015.
X.C., Jianjian Z., and C.H. contributed equally to this work.
This work was supported by grants from the National Natural Science Foundation of China [Grant 81470895] and the Science and Technology Commission of Shanghai Municipality [Grant 14140902000].
The authors disclose no conflict of interest.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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