Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane

Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (& LE;3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.

Automated summary

Acetaminophen (APAP) overdose can lead to severe liver injury and acute liver failure. The clinically approved antidote, N-acetylcysteine (NAC), has a limited therapeutic window. In this study, the researchers investigated the potential of activating the transcription factor Nrf2 as a treatment for APAP-induced liver injury. They found that short-term treatment with the Nrf2 activator sulforaphane did not effectively activate Nrf2 or protect against liver injury. They also compared the effectiveness of sulforaphane with NAC and found that NAC provided superior protection. These findings suggest that Nrf2 activators may not be suitable for treating APAP overdose compared to NAC.