On the Hyperthermia Induced by 2,4-Dinitrophenol

Bianchetti, Angelo; Pugliatti, C.; Jori, A.

doi:10.1159/000137108

Cited by 7 publications

(7 citation statements)

References 7 publications

(7 reference statements)

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“…The most notable, DNP, was initially used to synthesize explosives prior to World War I and later considered a promising anti-obesity drug after Maurice Tainter at Stanford University demonstrated the efficacy of this approach in obese humans [ 31 , 32 , 58 ]. By the early 1930s, DNP was widely taken as an over-the-counter medication for rapid weight loss in the US; however, reports of toxic side effects, including hyperthermia, cataract formation, and death, led to its withdraw from the market by the US Food and Drug Administration in 1938 [ 51 , 59 , 60 ]. Nonetheless, Russian soldiers continued to take DNP to stay warm on the Eastern Front during the frigid winters of World War II, and in recent years, there has been a resurgence in the illicit use of DNP by bodybuilders and athletes trying to shed fat and sculpt muscle [ 61 ].…”

Section: Therapeutic Relevance Of Mitochondrial Uncouplersmentioning

confidence: 99%

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Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Goedeke

Shulman

2021

Molecular Metabolism

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Background Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases. Scope of review In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic. Major conclusions Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.

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Section: Therapeutic Relevance Of Mitochondrial Uncouplersmentioning

confidence: 99%

“…Hyperthermia, due to systemic mitochondrial uncoupling, is a major contributing factor to the low therapeutic index of DNP and other systemic mitochondrial uncouplers [ 59 ]. To increase the therapeutic window of DNP, Perry et al.…”

Section: Therapeutic Relevance Of Mitochondrial Uncouplersmentioning

confidence: 99%

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Goedeke

Shulman

2021

Molecular Metabolism

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“…The increase in basal metabolic rate and body temperature seen in animals with thyrotoxicosis can also be produced by the administration of 2,4-dinitrophenol, an agent that uncouples oxidative phosphorylation (18). These similarities between the effect of dinitrophenol and thyrotoxicosis led us to study the effect of exposure to dinitrophenol in vivo on mitochondrial ADP transport.…”

Section: Resultsmentioning

confidence: 99%

“…One animal from each pair was injected intraperitoneally with sterile sodium dinitrophenolate (pH 7.4) in 0.9% NaCl (2 mg/kg of the freshly prepared solution), while the other was given 0.9% NaCl alone. After 90 min (18), the animals were killed, liver mitochondria were prepared, and ADP uptake and oxygen consumption were assayed. With dinitrophenol, as with both thyroxine and triiodothyronine, there was an increase in mitochondrial uptake of ADP (3.77 i 0.22 against 2.36 41 0.22 nmol/min per mg of protein; P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Stimulation of Mitochondrial Adenosine Diphosphate Uptake by Thyroid Hormones

Babior¹,

Creagan²,

Ingbar³

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone administered in vivo increased carrier-mediated (atractyloside-sensitive) ADP uptake by rat liver mitochondria. 3 Days after a single large dose of triiodothyronine (20 ;g/100 g of body weight), mitochondrial uptake of ADP measured at 60 was 2.35 4 0.17 nmol/min per mg of protein, compared with an uptake of 1.81 i 0.19 nmol/min per mg of protein in mitochondria from untreated rats (P < 0.025). Cyanide (1.33 mM) had no effect on ADP uptake by mitochondria from either untreated or triiodothyronine-treated animals. Uptake of ADP by mitochondria from thyroidectomized rats treated with thyroxine for 7 days was 2.89 4 0.40 nmol/min per mg in mitochondria from thyrotoxic rats (20 ug of thyroxine per 100 g per day) and 1.98 -0.22 nmol/min per mg in mitochondria from euthyroid rats (2 ug of thyroxine per 100 g per day) (P < 0.025). Mitochondria from both untreated and thyroid hormone-treated rats displayed a highly significant linear correlation between ADP uptake and ADP-dependent (i.e., state 3 minus state 4) oxygen consumption. There was, however, no difference in respiratory control ratios between mitochondria from euthyroid and thyrotoxic animals. Administration of dinitrophenol (2 mg/100 g) also stimulated carrier-mediated ADP uptake, but respiratory control of mitochondria from dinitrophenol-treated animals was virtually abolished. Triiodothyronine in vitro, at concentrations of 100 and 0.1 nM, appeared to inhibit rather than stimulate the uptake of mitochondrial ADP. The relationship between these observations and the clinical manifestations of thyrotoxicosis is discussed from the point of view of the possible effects of increased mitochondrial ADP transport on oxidative phosphorylation and adenosyl nucleotide metabolism.It has long been known that an increase in metabolic rate follows administration of a sufficient dose of thyroid hormone. Animals treated with large doses of thyroxine manifest an increased rate of oxygen consumption, a rise in body temperature, and a loss in weight, all consequent to an increase in the rate of oxidation of substrate (1, 2). Since most substrate oxidation takes place in mitochondria, many studies on the mechanism of action of thyroid hormone have involved these organelles. These studies have shown, for example, that * To whom to address correspondence. thyroid hormone increases the rate of mitochondrial oxidation of succinate, glutamate, ,-hydroxybutyrate, and isocitrate (3); the activity of the electron transport chain is increased without an increase in the concentrations of the chain components (4); and there is an increase in the activity of membrane-bound a-glycerophosphate dehydrogenase (5).In addition, thyroid hormone affects mitochondrial swelling (6, 7) and respiratory control (8), but these effects are only observed with rather large doses of hormone.The mitochondrion is composed of an outer membrane, an inner membrane, and two spaces: the intermembrane space, which lies between the membranes, and the matrix, which is enclosed within the inner me...

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“…Some of the most well-studied examples of mitochondrial protonophore uncouplers were discussed in a recent review and are illustrated in Figure . 2,4-Dinitrophenol (DNP, 1a ) is the most pertinent example as it was found to have weight-loss-inducing effects in humans, promoting upward of 50% increase in metabolism. − However, DNP caused adverse effects in some patients including increased body temperature, ,− cataracts, − and blindness, which led the U.S. Food and Drug Administration (FDA) to remove this drug from the market in 1938. Studies now indicate that the toxicity issues associated with DNP are due to a narrow therapeutic window, which may result from unwanted depolarization of nonmitochondrial membranes such as the plasma membrane. − In an effort to control DNP toxicity, Perry et al reported a controlled-release version that is orally bioavailable with an increased therapeutic range, reduced toxicity, improved insulin sensitivity in diabetic rats, and improvements in nonalcoholic fatty liver disease (NAFLD) phenotypes .…”

Section: Introductionmentioning

confidence: 99%

[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis

et al. 2020

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Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure−activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5-and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N−H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC 50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.

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On the Hyperthermia Induced by 2,4-Dinitrophenol

Cited by 7 publications

References 7 publications

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Stimulation of Mitochondrial Adenosine Diphosphate Uptake by Thyroid Hormones

[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis

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