The phytoestrogen equol protects mice against acetaminophen hepatotoxicity

Female mice have been resistant to acetaminophen (APAP)-induced liver injury, demonstrating that endogenous estrogens provide hepatoprotection, and it is expected that exogenous estrogens may also provide a similar effect. In the present study, we investigated the protective effects of the phytoestrogens equol and genistein against APAP-induced liver injury. Male CD-1 mice were intraperitoneally injected with APAP. Equol or genistein was administered 16 h prior and co-administered with APAP. The blood and liver samples were subjected to evaluation of hepatotoxicity, liver GSH levels and hepatic expression of inflammatory mediators. Phytoestrogen treatment effectively prevented APAP hepatotoxicity. Neither affected the early depletion of hepatic glutathione (GSH) caused by APAP, indicating that they did not affect the generation of <i>N</i>-acetyl-<i>p</i>-benzoquinone imine from APAP. This result was supported by <i>in vitro</i> studies with microsomes, which presented that both phytoestrogens inhibited CYP2E1 and CYP1A2 activities; however, high concentrations of these compounds were required. In contrast, genistein and, to a lesser extent, equol promoted the recovery of GSH after the depletion. Hepatic interleukin-6 expression was increased by after APAP administration, and the increase was suppressed by equol and genistein treatment, potentially contributing to hepatoprotection. The phytoestrogens equol and genistein protect mice from APAP hepatotoxicity, possibly by suppressing liver inflammation through their estrogen-dependent mechanisms.