Propylthiouracil, Perchlorate, and Thyroid-Stimulating Hormone Modulate High Concentrations of Iodide Instigated Mitochondrial Superoxide Production in the Thyroids of Metallothionein I/II Knockout Mice

Abstract

BackgroundIncreased oxidative stress has been suggested as one of the underlying mechanisms in iodide excess-induced thyroid disease. Metallothioneins (MTs) are regarded as scavengers of reactive oxygen species (ROS) in oxidative stress. Our aim is to investigate the effects of propylthiouracil (PTU), a thyroid peroxidase inhibitor, perchlorate (KClO4), a competitive inhibitor of iodide transport, and thyroid stimulating hormone (TSH) on mitochondrial superoxide production instigated by high concentrations of iodide in the thyroids of MT-I/II knockout (MT-I/II KO) mice.MethodsEight-week-old 129S7/SvEvBrd-Mt1tm1Bri Mt2tm1Bri/J (MT-I/II KO) mice and background-matched wild type (WT) mice were used.ResultsBy using a mitochondrial superoxide indicator (MitoSOX Red), lactate dehydrogenase (LDH) release, and methyl thiazolyl tetrazolium (MTT) assay, we demonstrated that the decreased relative viability and increased LDH release and mitochondrial superoxide production induced by potassium iodide (100 µM) can be relieved by 300 µM PTU, 30 µM KClO4, or 10 U/L TSH in the thyroid cell suspensions of both MT-I/II KO and WT mice (P<0.05). Compared to the WT mice, a significant decrease in the relative viability along with a significant increase in LDH release and mitochondrial superoxide production were detected in MT-I/II KO mice(P<0.05).ConclusionWe concluded that PTU, KClO4, or TSH relieved the mitochondrial oxidative stress induced by high concentrations of iodide in the thyroids of both MT-I/II KO and WT mice. MT-I/II showed antioxidant effects against high concentrations of iodide-induced mitochondrial superoxide production in the thyroid.

Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

“…Overexpression of MT in the human kidney reduced oxygen consumption, lowered cellular ATP levels, and decreased the oxidative phosphorylation capacity. 64,129 Metallothionein did not affect the number of mitochondria, but specifically reduced levels of cytochrome c oxidase subunit II proteins, which resulted in lower activity of Complex IV. 130 In addition, MT has been reported to inhibit superoxide generation and to dampen nitrosative damage, thereby preventing diabetes and its complications, including DCMP.…”

“…Metallothionein also suppressed ischemia–reperfusion‐induced myocardial apoptosis mediated by mitochondrial dysfunction . In terms of the downstream signaling of ROS and RNS stimuli, intrinsic apoptotic signaling leads to mitochondrial membrane permeabilization and releases cytochrome c into the cytosol via the JNK signaling pathway …”

“…Oxidative stress‐mediated damage to mitochondrial DNA was observed in patients with T2DM, MS, and atherosclerosis . In contrast, MT exerts antioxidant effects against mitochondrial superoxide generation, but the mechanism by which MTs affect the mitochondrial respiratory chain remain unknown. Overexpression of MT in the human kidney reduced oxygen consumption, lowered cellular ATP levels, and decreased the oxidative phosphorylation capacity .…”

“…In contrast, MT exerts antioxidant effects against mitochondrial superoxide generation, but the mechanism by which MTs affect the mitochondrial respiratory chain remain unknown. Overexpression of MT in the human kidney reduced oxygen consumption, lowered cellular ATP levels, and decreased the oxidative phosphorylation capacity . Metallothionein did not affect the number of mitochondria, but specifically reduced levels of cytochrome c oxidase subunit II proteins, which resulted in lower activity of Complex IV .…”

Comparative Study on the Binding Affinity of Methimazole and Propylthiouracil to Thyroid Peroxidase as an Anti-Thyroid Drug: An Insilico Approach

“…They also observed TSHR to be potent target for therapeutic study. A study done on PTU, KClO4, or TSH [87] revealed that these compounds reduced the oxidative stress due to high concentrations of iodide in the thyroids of both Metallothioneins(MTs) MT-I/II KO and WT mice. Bhabak and Mugesh in 2010 [88], and Manna, Roy and Mugesh in 2013 [89], reported Selenium analogues of ATDs to have better inhibitory effect compared to Sulphur based thinamide drugs on TPO suggesting that this selenium based drugs may be the next potential ATDs.…”