2,4-Dinitrophenol(CAS: 51-28-5) is used in the manufacture of dyes, wood preservatives, and as a pesticide. The acute (short-term) effects of 2,4-dinitrophenol in humans through oral exposure are nausea, vomiting, sweating, dizziness, headaches, and loss of weight. Chronic (long-term) oral exposure to 2,4-dinitrophenol in humans has resulted in the formation of cataracts and skin lesions, weight loss, and has caused effects on the bone marrow, central nervous system (CNS), and cardiovascular system. Limited or no information is available on the developmental, reproductive, or carcinogenic effects of 2,4-dinitrophenol in humans. EPA has not classified 2,4-dinitrophenol for carcinogenicity.
. J Med Toxicol. 2011 Sep;7(3):205-12. doi: 10.1007/s13181-011-0162-6.
2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death.
Grundlingh J(1), Dargan PI, El-Zanfaly M, Wood DM.
Author information: (1)Emergency Medicine, Whittington Hospital, London, UK.
2,4-Dinitrophenol (DNP) is reported to cause rapid loss of weight, but unfortunately is associated with an unacceptably high rate of significant adverse effects. DNP is sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncoupling of oxidative phosphorylation; the classic symptom complex associated with toxicity of phenol-based products such as DNP is a combination of hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Fatalities related to exposure to DNP have been reported since the turn of the twentieth century. To date, there have been 62 published deaths in the medical literature attributed to DNP. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarise the previous fatalities associated with exposure to DNP.
DOI: 10.1007/s13181-011-0162-6 PMCID: PMC3550200 PMID: 21739343 [Indexed for MEDLINE]
. Cells. 2019 Mar 23;8(3):280. doi: 10.3390/cells8030280.
2,4 Dinitrophenol as Medicine.
Author information: (1)Mitochon Pharmaceuticals, Inc., 970 Cross Lane, Blue Bell, PA 19422, USA. [email protected]
In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and "morning sickness" anti-nausea medication targeting pregnant women in the 1950's. The "thalidomide babies" became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of "social responsibility" allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle's physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer's Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for "metabesity", an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP's induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80's years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).
DOI: 10.3390/cells8030280 PMCID: PMC6468406 PMID: 30909602 [Indexed for MEDLINE]
. Med J Aust. 2020 May;212(9):434-434.e1. doi: 10.5694/mja2.50528. Epub 2020 Mar 1.
2,4-Dinitrophenol exposures and deaths in Australia after the 2017 up-scheduling.
Cairns R(1)(2), Raubenheimer J(1), Brown JA(2)(3), McArdle K(2)(4), Buckley NA(1)(2).
Author information: (1)University of Sydney, Sydney, NSW. (2)New South Wales Poisons Information Centre, Children's Hospital at Westmead, Sydney, NSW. (3)Centre for Big Data Research in Health, UNSW Sydney, Sydney, NSW. (4)Gosford Hospital, Gosford, NSW.
DOI: 10.5694/mja2.50528 PMID: 32115701 [Indexed for MEDLINE]
. Arch Toxicol. 2020 Apr;94(4):1071-1083. doi: 10.1007/s00204-020-02675-9. Epub 2020 Feb 20.
Diet aid or aid to die: an update on 2,4-dinitrophenol (2,4-DNP) use as a weight-loss product.
Sousa D(1), Carmo H(1), Roque Bravo R(1), Carvalho F(1), Bastos ML(1), Guedes de Pinho P(2), Dias da Silva D(3).
Author information: (1)UCIBIO/REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. (2)UCIBIO/REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. [email protected]
(3)UCIBIO/REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. [email protected]
During the last decades, we have witnessed unparalleled changes in human eating habits and lifestyle, intensely influenced by cultural and social pressures. Sports practice became strongly implemented in daily routines, and visits to the gym peaked, driven by the indulgence in intensive 'weight-loss programs'. The pledge of boasting a healthy and beautiful body instigates the use of very attractive 'fat burners', which are purportedly advertised as safe products, easily available in the market and expected to quickly reduce body weight. In this context, the slimming properties of 2,4-dinitrophenol (2,4-DNP) galvanised its use as a weight-loss product, despite the drug ban for human consumption in many countries since 1938, due to its adverse effects. The main symptoms associated with 2,4-DNP intoxication, including hyperthermia, tachycardia, decreased blood pressure, and acute renal failure, motivated a worldwide warning, issued by the Interpol Anti-Doping Unit in 2015, reinforcing its hazard. Information on the effects of 2,4-DNP mainly derive from the intoxication cases reported by emergency care units, for which there is no specific antidote or treatment. This review provides a comprehensive update on 2,4-DNP use, legislation and epidemiology, chemistry and analytical methodologies for drug determination in commercial products and biological samples, pharmacokinetics and pharmacodynamics, toxicological effects, and intoxication diagnosis and management.
DOI: 10.1007/s00204-020-02675-9 PMID: 32078021 [Indexed for MEDLINE]
. J Forensic Sci. 2020 Jan;65(1):183-188. doi: 10.1111/1556-4029.14154. Epub 2019 Aug 20.
Analysis of 2,4-Dinitrophenol in Postmortem Blood and Urine by Gas Chromatography-Mass Spectrometry: Method Development and Validation and Report of Three Fatalities in the United States.
Geraldo de Campos E(1)(2), Fogarty M(1), Spinosa De Martinis B(2), Kerr Logan B(1)(3).
Author information: (1)Center for Forensic Science Research and Education, 2300 Stratford Avenue, Willow Grove, PA. (2)Faculdade de Filosofia, Ciencias e Letras de Ribeirao Preto, University of Sao Paulo, 3900 Bandeirantes Avenue, Ribeirao Preto, Brazil. (3)NMS Labs, 200 Welsh Road, Horsham, PA.
2,4-dinitrophenol (2,4-DNP) is a compound used in the early 1900s as a weight-loss drug but later prohibited due to its severe adverse effects, including death. It has however been attracting interest, due to its weight-loss properties, and appears to be re-emerging in forensic casework. As 2,4-DNP is available for use in industry and as a pesticide and easily accessible online, the dissemination of this drug can be fast. The compound exerts its effects through inhibition of ATP synthesis, and corresponding thermogenic energy loss which can be fatal. A method for qualitative and quantitative analysis of 2,4-DNP in blood and urine specimens using GC-MS with hydrogen as carrier gas is described. The method was validated and displayed acceptable performance parameters with linearity (R2 higher than 0.998), inter-assay imprecision (lower than 10.6%), intra-assay imprecision (lower than 10.7%), and extraction efficiency (92.1%). Stability of 2,4-DNP in blood and urine was studied, and the drug was stable up to 30 days refrigeration or frozen. Six cases in United States suspected to be related to 2,4-DNP were analyzed. Three cases were found to be positive for 2,4-DNP. Concentrations of 2,4-DNP were in the range of 61.6-220 mg/L in urine and <3-114 mg/L in blood. Based on our findings, we suggest that medical examiners and forensic toxicologists be aware of the reappearance of 2,4-DNP, including this compound as a target in death investigations related to weight-loss drugs.
DOI: 10.1111/1556-4029.14154 PMID: 31430392 [Indexed for MEDLINE]