Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is known to confer antioxidant protection in vivo. Rather than directly reacting with free radicals, however, SFN works by inducing Nrf2, a transcription factor that binds to the promoter regions of several known antioxidant genes and enhances detoxification. Because oxidative stress is a major contributor to acetaminophen (APAP)-induced hepatotoxicity, SFN may defend the liver against APAP overdose by activating the Nrf2 pathway and increasing endogenous antioxidant response. To test this hypothesis, mice were pre-treated with SFN for four days, injected with APAP on the fifth day, and sacrificed shortly thereafter. APAP overdose caused massive hepatic injury, as shown by increases in serum liver enzyme activity and lipid peroxidation. APAP overdose also manifested as decreases in total glutathione and glutathione reductase activity. SFN administration clearly prevented these manifestations of liver injury, however: increases in serum liver enzyme activity and lipid peroxidation were blunted, while total glutathione and glutathione reductase activity remained similar to those of control animals. SFN treatment did not affect the catalytic activity of acetaminophen-metabolizing enzyme CYP2E1, but did increase nuclear accumulation of Nrf2, suggesting that SFN acts primarily through the Nrf2 pathway. In summary, these data support the hypothesis that sulforaphane attenuates acute acetaminophen-induced liver injury. This decrease in injury results from the increased availability of glutathione to react with toxic metabolites of acetaminophen.
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Sulforaphane prevents acetaminophen-induced hepatic injury in mice.
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