Activation of autophagy protects against acetaminophen-induced hepatotoxicity

Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria–damage–induced cell death. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP–induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP–induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP–induced autophagy was suppressed by N –acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP–induced autophagy. Pharmacological inhibition of autophagy by 3–methyladenine or chloroquine further exacerbated APAP–induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP–induced hepatotoxicity. Conclusion : APAP overdose induces autophagy, which attenuates APAP–induced liver cell death by removing damaged mitochondria. (Hepatology 2012)