Iron-induced changes in nitric oxide and superoxide radical generation in rat liver after lindane or thyroid hormone treatment

Abstract

The involvement of cytosolic nitric oxide (NO) and mitochondrial superoxide radical (O 2 −) production was evaluated as a mechanism triggering liver oxidative stress in lindane (40 mg/kg) or l-3,3′,5-triiodothyronine (T 3, 0.1 mg/kg for 2 consecutive days) treated animals (male Sprague–Dawley rats) subjected to iron overload (200 mg/kg). Lindane and iron led to 504 and 210% increases in the content of hepatic protein carbonyls as an index of oxidative stress, with a 706% enhancement being produced by their combined administration. T 3 did not alter this parameter, whereas iron overload increased the content of protein carbonyls by 116% in hyperthyroid rats. Lindane increased NO generation by 106% without changes in generation of O 2 −, whereas iron enhanced both parameters by 109 and 80% over control values, respectively, with a net 33 and 46% decrease, respectively, being elicited by the combined treatment related to iron overload alone. Hyperthyroidism increased liver NO (69%) and O 2 − (110%) generation compared to controls, effects that were either synergistically augmented or suppressed by iron overload, respectively. The in vitro addition of iron (1 μmol/mg protein) to liver cytosolic fractions from euthyroid (97%) and hyperthyroid (173%) rats also enhanced NO generation. The effects of iron overload on mitochondrial O 2 − production by hyperthyroid rats were reproduced by the in vitro addition of 1 μmol iron/mg protein and abolished by the in vivo pretreatment with the iron chelator desferrioxamine (500 mg/kg). It is concluded that liver oxidative stress induced by iron overload is independent of NO and O 2 − production in lindane-treated rats, whereas in hyperthyroid animals NO generation is a major factor contributing to this redox imbalance.