Derangement of Kupffer cell functioning and hepatotoxicity in hyperthyroid rats subjected to acute iron overload

Abstract

Liver oxidative stress, Kupffer cell functioning, and cell injury were studied in control rats and in animals subjected to L-3,3′,5-tri-iodothyronine (T₃) and/or acute iron overload. Thyroid calorigenesis with increased rates of hepatic O₂ uptake was not altered by iron treatment, whereas iron enhanced serum and liver iron levels independently of T₃. Liver thiobarbituric acid reactants formation increased by 5.8-, 5.7-, or 11.0-fold by T₃, iron, or their combined treatment, respectively. Iron enhanced the content of protein carbonyls independently of T₃ administration, whereas glutathione levels decreased in T₃- and iron-treated rats (54%) and in T₃Fe-treated animals (71%). Colloidal carbon infusion into perfused livers elicited a 109% and 68% increase in O₂ uptake in T₃ and iron-treated rats over controls. This parameter was decreased (78%) by the joint T₃Fe administration and abolished by gadolinium chloride (GdCl₃) pretreatment in all experimental groups. Hyperthyroidism and iron overload did not modify the sinusoidal efflux of lactate dehydrogenase, whereas T₃Fe-treated rats exhibited a 35-fold increase over control values, with a 54% reduction by GdCl₃ pretreatment. Histological studies showed a slight increase in the number or size of Kupffer cells in hyperthyroid rats or in iron overloaded animals, respectively. Kupffer cell hypertrophy and hyperplasia with presence of inflammatory cells and increased hepatic myeloperoxidase activity were found in T₃Fe-treated rats. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effects of iron, which seems to be related to the development of a severe oxidative stress status in the tissue, thus contributing to the concomitant liver injury and impairment of Kupffer cell phagocytosis and particle-induced respiratory burst activity.