PT - JOURNAL ARTICLE AU - Xiaosong Chen AU - Jianjian Zhang AU - Conghui Han AU - Huijuan Dai AU - Xianming Kong AU - Longmei Xu AU - Qiang Xia AU - Ming Zhang AU - Jianjun Zhang TI - A Sexual Dimorphism Influences Bicyclol-Induced Hepatic Heat Shock Factor 1 Activation and Hepatoprotection AID - 10.1124/mol.114.097584 DP - 2015 Apr 21 TA - Molecular Pharmacology PG - mol.114.097584 4099 - http://molpharm.aspetjournals.org/content/early/2015/04/21/mol.114.097584.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/04/21/mol.114.097584.full AB - Bicyclol is a synthetic hepatoprotectant widely used in the clinical practice, but resistance to its treatment is often observed. We found that the hepatoprotective effect of bicyclol was greatly compromised in female or 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 by using acute liver damage models. Inducible knockout by Cre-loxp system was employed 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 (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 are associated with very low testosterone levels, our results give a possible explanation for the clinical variation in bicyclol-induced hepatoprotection, as well as practicable solutions to it.