Superoxide Radical Generation, NADPH Oxidase Activity, and Cytochrome P-450 Content of Rat Liver Microsomal Fractions in an Experimental Hyperthyroid State: Relation to Lipid Peroxidation*

Abstract

The effect of thyroid hormone treatment on hepatic microsomal functions related to NADPH-dependent electron transfer reactions was studied in rats given 0.1 mg T3/kg BW for 1, 2, 3, and 7 consecutive days. This treatment resulted in increased rates of O2-. generation by microsomal fractions, concomitantly with an enhancement in NADPH oxidase activity and decreased cytochrome P-450 content, in livers exhibiting increased respiration. Subsequent studies showed elevated levels of malondialdehyde in microsomal fractions and liver homogenates, as well as augmented chemiluminescent response in the latter system. These results indicate that the calorigenic effect of T3 on the liver tissue is accompanied by a stimulation of microsomal functions involving univalent reduction of oxygen. This cellular response might lead to a greater lipid peroxidative rate and cytochrome P-450 loss as secondary events of thyroid hormone action.

Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress

“…Nongenomic signaling occurring via 3,5-diiodothyronine (3,5-T 2 ) and T 3 may also be operative, leading to allosteric activation of cytochrome c oxidase (21). The net result of the activation of both signaling pathways is the enhancement in the rate of O 2 consumption of target tissues such as liver (22), which may be contributed by secondary processes induced by T 3 such as (i) induction of uncoupling proteins (23); (ii) energy expenditure due to futile cycles coupled to increase in catabolic and anabolic pathways (24); (iii) loss of energy due to higher active cation transport (16,19); and (iv) O 2 equivalents used in the generation of mitochondrial ROS ( Fig. 1; 25, 26).…”

“…In addition, Kupffer cells isolated from acutely T 3 -treated rats exhibited upregulation of UCP2 mRNA, which may limit mitochondrial ROS production by these cells (30). Consequently, T 3 -induced ROS production is associated with diminution in antioxidant defenses (28,(31)(32)(33), thus increasing the oxidative stress status in the liver with enhancement of hepatic lipid peroxidation (22,28,(34)(35)(36), protein carbonylation (37), and DNA oxidation (38). This pro-oxidant state induced in the liver of experimental animals by thyroid hormone administration is considered as a mild redox alteration, considering the lack of occurrence of morphological changes in liver parenchyma, except for significant hyperplasia and hypertrophy of Kupffer cells ( Fig.…”

Flow‐cytometric analysis of reactive oxygen species in peripheral blood mononuclear cells of patients with thyroid dysfunction

“…The hyperthyroid patients recruited for the study had significantly higher levels of fT 4 (72.4 6 20.2 pmol/l) and suppressed TSH (0.020 6 0.015 mIU/ml). Although, we had recruited patients who were biochemically proven to be thyrotoxic, there were variations in the hormonal levels.…”

“…Thyroid hormones are the major regulators of oxidative energy metabolism (1) at the level of the mitochondrion (2) inducing increase in oxygen consumption (3) and heat production in mammalian tissues (4,5) and are responsible for increased metabolic rate (6) in hyperthyroidism. Therefore, excess secretion of thyroid hormone or hyperthyroidism leads to hypermetabolic state, causing accelerated mitochondrial electron transport that could enhance generation of reactive oxygen species (ROS), thereby leading to oxidative stress.…”

“…Studies conducted in rat models have also demonstrated an increase in free radical production and lipid peroxide levels during hypermetabolic state (4,7,8), while the hypometabolic state induced by hypothyroidism is associated with a decrease in free radical production (9) and lipid peroxidation products (10). However, alterations in ROS levels have not been demonstrated in the cells or tissues of patients having thyroid dysfunction.…”