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Involvement of Xanthine Oxidase in Oxidative Stress and Iron Release during Hyperthermic Rat Liver Perfusion¹

Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 [R. H. P., A. S.]; Section of Medical Education, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee 37614 [J. H. K.]; and Ellis Fischel Cancer Center, University of Missouri Health Sciences Center, Department of Surgery, Columbia, Missouri 65203 [J. L. S.]

The hepatotoxic effects of hyperthermia have been proposed to be related to lipid peroxidation as a consequence of oxidative stress. This can result from exposure of the cell to "radical oxygen" species such as the superoxide and hydrogen peroxide generated by the activity of the oxidase form (type O) of xanthine oxidase (XO), which is converted to that form by perfusion of the liver at hyperthermic temperatures. These radical species are not reactive enough in themselves to cause cell damage but require the presence of a catalyst such as low molecular weight chelated iron. In these studies, ferritin was shown to be a source of iron for the oxidative stress of hyperthermia. (a) Iron was released from ferritin in vitro by the activity of rat liver XO. The rate of iron release from ferritin in this incubation system was a function of the amount of type O XO present and the temperature. Inclusion of allopurinol or superoxide dismutase in the incubation resulted in significantly lower rates of iron release. (b) Livers from Sprague-Dawley rats were perfused at 42.5° and 37°C for 1 h. During the recirculating perfusion, loss of iron from the liver into the perfusate was significantly greater (P < 0.05) at 42.5°C than at 37°C. Also, there was a pronounced increase in the lactate dehydrogenase and aspartate aminotransferase enzymes in the perfusate during perfusion at 42.5°C. Furthermore, intrahepatic levels of low molecular weight chelated iron were significantly (P < 0.05) increased following perfusion at 42.5°C. All these responses were abrogated by the inclusion of allopurinol in the perfusate. (c) Oxidative stress, assessed by the efflux of glutathione and oxided glutathione from the liver at 42.5° and 37°C, was significantly (P < 0.05) increased at the hyperthermic temperature. This oxidative stress was inhibited by iron chelation and allopurinol. These results demonstrate that there is a causal relationship between the generation of superoxide by type O XO produced by hyperthermic perfusion and mobilization of iron from ferritin to form a pool of low molecular weight chelated iron. This iron pool in combination with active oxygen species leads to oxidative stress and lipid peroxidation.

¹ Supported by National Cancer Institute Grant CA41316.

² To whom requests for reprints should be addressed, at: Ellis Fischel Cancer Center, University of Missouri, 115 Business Loop 70 West, Columbia, MO 65203.

Received 9/25/91. Accepted 1/20/92.

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