Uncoupling of the xanthine dehydrogenase system

The cytosolic enzyme xanthine dehydrogenase catalyses the oxidation of hypoxanthine and xanthine to uric acid. It is thought to be located predominantly in the liver, small intestine and capillary endothelium in man [9]. However, the distribution is different in other species. In healthy tissue, most of the enzyme is present as the D form , which transfers electrons to NAD+  

However, about 10% of the enzyme is present as an oxidase ( O-type ) form, which transfers electrons to molecular oxygen to form O - or H2O2  

Recently, we have provided evidence that hypoxic reperfusion injury occurs in the inflamed human joint [2,12,13]. Joint movement in patients with RA produces intra-articular pressures in excess of the synovial capillary perfusion pressure. This phenomenon does not occur in normal joints, where the pressure remains subatmospheric throughout a movement cycle. During exercise of the inflamed joint, the intra-articular pressure is transmitted directly to the synovial membrane vasculature, producing occlusion of the superficial synovial capillary bed and ischaemia. Reperfusion of the synovial membrane occurs when exercise is stopped. Recently, electron spin resonance spectroscopy with spin trapping was employed to demonstrate that synovial tissue from a patient with RA generated ROI following a transient hypoxic 

Uncoupling of mitochondrial and endoplasmic reticulum electron-transport chains 

The endoplasmic reticulum electron-transport system (NADPH-cytochrome P-450 reductase) can also generate [18]. This system, which is often responsible for the metabolism of foreign compounds, is selectively distributed in a wide variety of cell types. Its presence in hepatocytes is particularly important, since drugs are often metabolised at this site. In this system, a single electron is transferred from reduced flavin to a cytochrome P-450-substrate complex. A second electron is then transferred through this complex to O2. Production of O - may occur through auto-oxidation of the partially reduced flavin cofactor or because of uncoupling of electrons from the enzyme-substrate complex to 02 [19]. 

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