Toxicological sciences : an official journal of the Society of Toxicology
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Oxidative stress and mitochondrial dysfunction play an important role in acetaminophen (APAP)-induced hepatocyte cell death. However, exact mechanisms involved in the process are controversial, in part, because of the disparity in findings between in vitro and in vivo studies. A major difference in this context is the oxygen tension, with cells in culture being exposed to 21% oxygen, whereas those in the liver experience a gradient from 3 to 9% oxygen. ⋯ Furthermore, dihydrorhodamine fluorescence was significantly attenuated at 10% oxygen. Cells cultured at 5% oxygen were also protected but showed evidence of hypoxia (accumulation of lactate and nuclear translocation of hypoxia-inducing factor-1α). These results suggest that oxygen tension can modulate hepatocyte responses to APAP, with low physiological levels (10%) decreasing mitochondrial oxidant stress and delaying hepatocyte cell death.