https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840080324

Oxidant stress during reperfusion of ischemic liver: no evidence for a role of xanthine oxidase.

Mechanisms of hypoxic cell injury. Summary of the symposium presented at the 1990 annual meeting of the Society of Toxicology.

The mechanism of reoxygenation injury was studied in primary cultures of isolated hepatocytes from rat liver. Reoxygenation injury, which affected up to 80% of the hepatocytes, was only inducible within a certain time window of the anaerobic incubation. Reintroduction of oxygen before this vulnerable period ensured the survival of the hepatocytes. After the vulnerable period upon reintroduction of oxygen the hepatocytes continued to die in the same way as the anaerobic control. Allopurinol had no effect on reoxygenation injury. From the inhibitors of the mitochondrial respiratory chain, both cyanide and antimycin A increased injury while rotenone was without significant effect on injury. Reoxygenation injury was significantly diminished by superoxide dismutase, but not by catalase. When added together, superoxide dismutase and catalase completely prevented reoxygenation injury. The results demonstrate that reoxygenation injury in hepatocytes is mediated by the combined action of both O2- and H2O2. These reduced oxygen species are not liberated by xanthine oxidase but possibly originate from the mitochondrial respiratory chain.

Reoxygenation injury in rat hepatocytes: mediation by O2/H2O2 liberated by sources other than xanthine oxidase.

Inhibition of ischemia and reflow-induced liver injury by an SOD derivative that circulates bound to albumin.

Significance: Cells sense and respond to a shortage of oxygen by activating the hypoxia-inducible transcription factors HIF-1 and HIF-2 and evoking adaptive responses. Recent Advances: Mitochondria are at the center of a hypoxia sensing and responding relay system. Critical Issues: Under normoxia, reactive oxygen species (ROS) and nitric oxide (NO) are HIF activators. As their individual flux rates determine their diffusion-controlled interaction, predictions how these radicals affect HIF appear context-dependent. Considering that the oxygen requirement for NO formation limits its role in activating HIF to conditions of ambient oxygen tension. Given the central role of mitochondrial complex IV as a NO target, especially under hypoxia, allows inhibition of mitochondrial respiration by NO to spare oxygen thus, raising the threshold for HIF activation. HIF targets seem to configure a feedback-signaling circuit aimed at gradually adjusting mitochondrial function. In hypoxic cancer cells, mitochondria...

Sensors, Transmitters, and Targets in Mitochondrial Oxygen Shortage—A Hypoxia-Inducible Factor Relay Story

The biliary GSSG efflux rate of normoxic perfused rat liver was 1.5 +/- 0.2 nmol/min/g liver wet weight. The GSSG efflux rate as indicator for the flux through the glutathione peroxidase reaction and, therefore, for an oxidative loading increased with the extent of hypoxia. 2.6 +/- 0.5 nmol/min/g were released from the severely hypoxic liver. The hydroxyl radical scavenger formate as well as the xanthine oxidase inhibitor allopurinol reduced the efflux rate of GSSG. GSH was released from the perfused liver at a rate of 15.5 nmol/min/g which was nearly unchanged in severe hypoxia. The high rate of glucose liberation from the hypoxic liver declined to almost that of the normoxic organ in the presence of formate. There is an 'oxidative stress' during hypoxic liver perfusion which probably originates from increased generation of activated oxygen species in the degradation of purine nucleotides.

Lutz Räder

Papers

Formation of activated oxygen in the hypoxic rat liver.