Hyperthermic liver toxicity: A role for oxidative stress

Abstract Rat livers were perfused at 37°C, 41°C, 42°C, 42.5°C, and 43°C for 2 hr. Among perfusate constituents analyzed were urea, total amino acids, N‐acetyl‐β‐glucosaminidase (NAG), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malonaldehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), allantoin, potassium, phosphate, and glucose. After perfusion, livers were homogenized and analyzed for xanthine oxidase (XO) activity, GSH content, and lysosomal lability. Perfusate AST, LDH, NAG, potassium, glucose, and phosphate increased significantly with time, and there were significant differences in the final values between 37°C and 42°C, 42.5°C, and 43°C ( P < .05). GSH levels increased significantly at all temperatures after 90 and 120 min, whereas GSSG levels differed significantly at 60, 90, and 120 min for 37°C vs. 42°C, 42.5°C, and 43°C ( P < .05). Mean MDA levels at 37°C differed from those at 41°C and 43°C ( P < .05) at each temperature. Allantoin levels increased significantly with time of perfusion; mean levels at 37°C were significantly different from mean levels at each temperature at 60,90, and 120 min. GSH liver tissue levels decreased with perfusion at hyperthermic temperatures; mean values at 41°C, 42°C, 42.5°C, and 43°C differed from 37°C mean values ( P < .01). Type O XO increased after 120 min perfusion from 6.4% ± 2.0% at 37°C to 55% ± 30%, 43% ± 27%, and 63% ± 29% at 42°C, 42.5°C, and 43°C, respectively. Lysosomal lability increased after perfusion at 42.5°C. There was a significant increase in nonsedimentable NAG activity at 42.5°C ( P < .05). These data support the premise that hyperthermic toxicity to the liver may be a consequence of oxidative stress brought about by enhanced adenosine triphosphate (ATP) consumption and conversion of XO to type O. Such conversion results in superoxide formation and subsequent depletion of cellular GSH, labilization of the lysosomes, and plasma membrane damage.