Structure, function and evolution of multidomain proteinsChristine Vogel, Matthew Bashton, Nicola D Kerrison,Cyrus Chothia and Sarah A Teichmann Proteins are composed of evolutionary units called domains; the residues in the proteins of completely sequenced genomes majority of proteins consist of at least two domains. These using homology-based methods. These include the profile
Kfd.plJ. Med. Toxicol. (2011) 7:205–212DOI 10.1007/s13181-011-0162-6 2,4-Dinitrophenol (DNP): A Weight Loss Agentwith Significant Acute Toxicity and Risk of Death Johann Grundlingh & Paul I. Dargan &Marwa El-Zanfaly & David M. Wood Published online: 8 July 2011 # American College of Medical Toxicology 2011 Abstract 2,4-Dinitrophenol (DNP) is reported to cause Keywords Dinitrophenol . Weight loss . Toxicity. Fatality rapid loss of weight, but unfortunately is associated with anunacceptably high rate of significant adverse effects. DNPis sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncouplingof oxidative phosphorylation; the classic symptom complex The pharmacologic treatment of obesity has been challenging.
associated with toxicity of phenol-based products such as Previously, amphetamine derivatives, such as dexflenflur- DNP is a combination of hyperthermia, tachycardia, amine, fenfluramine and phentermine, were used as centrally diaphoresis and tachypnoea, eventually leading to death.
active appetite suppressants; however, their use is associated Fatalities related to exposure to DNP have been reported with valvular heart disease and the development of pulmonary since the turn of the twentieth century. To date, there have hypertension. Sibutramine (Reductil™ Abbott Laboratories), been 62 published deaths in the medical literature attributed a newer centrally active appetite suppressant and the lipase to DNP. In this review, we will describe the pattern and inhibitor orlistat (Xenical™, Roche) are currently being used pathophysiology of DNP toxicity and summarise the as ‘diet pills', but have unpleasant side effects. However, for previous fatalities associated with exposure to DNP.
the majority of individuals with morbid obesity (body massindex >35 kg/m2), obesity surgery (‘gastric banding') is oftenthe treatment modality of choice, particularly in those associated severe co-morbidities . Regular use of 2, Emergency Medicine, Whittington Hospital,London, UK 4-dinitrophenol (DNP) is reported to cause rapid loss ofweight, but unfortunately is associated with an unacceptably P. I. Dargan D. M. Wood high rate of significant side effects ].
Guy's and St Thomas' NHS Foundation Trust The first death due to DNP (C 6H4N2O5) was reported in 's Health Partners, 1918 and was secondary to occupational exposure Currently marketing of DNP, which is predominately P. I. Dargan D. M. Wood through the internet, is targeted towards primarily body King's College London, builders who are attempting to lose fat but retain muscle bulk. Additionally, it is widely available on the internet and is marketed as a ‘safe weight loss' drug. Individuals are Emergency Medicine, Northwick Park Hospital, able to purchase ‘large quantities', such as kilograms of DNP powder or hundreds/thousands of DNP-containing tablets. There are many regimes for taking the drug, all of Medical Toxicology Office, which rely on the metabolic stimulatory effects of the drug 2nd Floor, Bermondsey Wing, It has a small therapeutic index and is extremely Guy's Hospital, Great Maze Pond, dangerous in overdose. In this review, we will summarise London, SE1 9RT, UKe-mail: [email protected] the pharmacology of DNP, the potential mechanisms for its J. Med. Toxicol. (2011) 7:205–212 toxicity and the clinical evidence of harm associated with In 1981, a physician (Dr. Bachynsky) in TX, USA the use of DNP.
processed industrial DNP into tablets which he marketed/dispensed under the trade name ‘Mitcal' through his privateweight loss clinic ]. He advertised that weight loss occurred using ‘Mitcal' through a mechanism he calledintracellular hyperthermia therapy. It is alleged in subse- The National Center for Biotechnology Information quent court proceedings that over 14,000 people were (PubMed) system was searched utilising the search treated by Dr. Bachynsky. Individuals using Mitcal started terms ‘dinitrophenol', ‘dinitrophenol overdose' and ‘dinitro- reporting adverse effects, such as fever, shortness of breath phenol death' in titles and abstracts. All the relevant abstracts and sweating, to the US Food and Drugs Administration in were screened by one author (JG) and those that did not late 1982. Additionally, there was a fatality associated with describe death(s) due to DNP were excluded from the pool of an intentional overdose of ‘Mitcal' in 1984. Following results. All the remaining articles were retrieved and further investigation, Dr. Bachynsky was convicted in 1986 scrutinized to ensure they convincingly described death(s) of drug law violations, fined and prohibited from dispens- due to DNP. All articles describing deaths due to other ing DNP to any patients. However, he continued to use compounds similar to DNP (e.g. dinitro-crescol) were DNP for a variety of different ‘medicinal claims' and was excluded. Citations and references of the remaining articles eventually jailed for fraud in 2008 in the USA in relation to were searched, retrieved and evaluated in the same way as the the marketing of a company that was developing DNP original search results. Additional online searches for suppli- being used in Europe as a cancer treatment known as ers of DNP were done using an internet search engine intracellular hyperthermia therapy ].
(Google) with the terms ‘dinitrophenol' and ‘dinitrophenol The UK Food Standard Agency issued a warning in weight loss'.
2003, labelling DNP as ‘not fit for human consumption'.
This warning was aimed specifically at bodybuilders, toavoid its use due to significant potential for short-term and History of Dinitrophenol long-term harm, following the hospitalisation of a Finishbodybuilder after having taken DNP [ The French used DNP in the manufacture of munitions Despite this, DNP remains widely available and as during the First World War [Since then, it has also discussed below in more detail, can be purchased over the been used as a dye, wood preserver, herbicide and internet, particularly from online pharmacies. Additionally, photographic developer. It was Maurice Tainter at Stanford there are instructions for the synthesis of DNP online for self- University in 1933 who discovered that the human manufacture. As noted above, DNP has been banned as a consumption of DNP led to significant weight loss and weight loss drug in the USA, and in the UK, it has been soon it was popularised as a weight loss drug . It was labelled as a hazardous chemical under the Clean Air Act included in over-the-counter medications and was sold to , ]. Despite this legislation and warnings of harm the public without requiring a prescription.
associated with its use, reports of deaths due to the use of Its use for those wishing to lose weight was encouraged by DNP have increased in the last few years (Fig. and the reports of rapid, safe weight loss , DNP can cause a significant increase in the basal metabolic rate , ]. Thisleads to weight loss by burning more fat and carbohydrates and weight loss of up to 1.5 kg per week is reported without significant side effects. However, there seems to besignificant variation in individual responses with an average metabolic rate increase of 11% for every 100 mg of DNP when taken regularly As more side effects, especially cataracts, were reported, DNP was labelled as ‘extremely dangerous and not fit for human consumption' by the Federal Food, Drug and Cosmetic Act of 1938 , After 1938, medical prescription of DNP stopped and cases of poisoning due to medical intake were no longer reported, but case reports of deaths associated with the 1910- 1921- 1931- 1941- 1951- 1961- 1971- 1981- 1991- 2001- 1940 1950 1960 1970 1980 ingestion of DNP still emerged , ]. It is anecdotally reported to have been prescribed to the Russian soldiersduring World War II to keep them warm [ Fig. 1 Graphical presentation of DNP-related deaths by decade J. Med. Toxicol. (2011) 7:205–212 Table 1 Summary of previously published fatalities relating to exposure to DNP including basic demographics, amount of exposure and maximaltemperature recorded pre-death Maximum temperature 40.5°C (104.9°F) > 43°C (>110°F) 300 mg over 6 weeks 40.4°C (104.8°F) 16 days after start of trial 2.88 g over 5 days 7 days after first dose ∼10 g over 6 weeks 5 days after admission 40.9°C (105.7°F) 5.4 g over 46 days 20 h after admission 40.9°C (105.6°F) 38.5°C (101.4°F) 2.4 g over 4 days 17 h after last dose > 40°C (>104°F) 3 h after presentation 50 min after presentation Unknown over 1 week 8 h after presentation 37.8°C (100.0°F) 39.5°C (103.1°F) 38.5°C (101.3°F) NR (not recorded) last decade has seen the highest number of case reports from rather than for generic weight loss. A typical regimen would death due to intentional dinitrophenol overdose (Table include starting with one capsule of DNP for the first few daysfollowed by increasing doses to a recommended maximum of400 mg/day, which is then used for up to 2 weeks in duration The Role of the Internet in Sourcing and Supplying , These regimens may also include the use of anabolic steroids and/or thyroxine to increase muscle bulk. There isalso the suggestion that ‘crystalline' DNP is more potent Nowadays, DNP is sold mostly over the internet under a than ‘regular' DNP and therefore users should ensure they number of different names such as ‘DNP', ‘Dinosan', are aware of which type they are using and additionally, ‘Dnoc', ‘Solfo Black', ‘Nitrophen', ‘Aldifen' and ‘Chemox'.
should limit the dose of crystalline DNP to no more than The chemical is a yellow crystalline powder that has a sweet, 200 mg/day. These websites additionally describe the musty odour and is soluble in water. The dose of DNP per potential toxicity associated with the use of DNP including capsule varies from website to website but it is most the potential for hyperthermia and death. Advice is provided commonly sold as either 100- or 200-mg capsules. Some to users on how to prevent hyperthermia developing, internet sites have DNP available in bulk quantities, allowing including use of air conditioning/fans and only exercising users to purchase kilograms of DNP powder or hundreds/ in cool areas whilst on the DNP phase of a ‘treatment cycle' thousands of DNP-containing tablets, as well as offering free and carrying a thermometer to monitor body temperature [ anabolic steroids and thyroxine to use in combination with They recommend that should body temperature rise above 38.9°C (102°F), the user should ‘lower the DNP dose, take a Websites often offer some advice for users around the use very cold bath and ensure adequate hydration with water and of DNP, although this is often targeted towards bodybuilders J. Med. Toxicol. (2011) 7:205–212 The marketed and desired beneficial effect of weight loss is doses [Pyruvic acid is aerobically metabolised to H2O reportedly not rapid enough for some individuals, and and CO2, but results in the production of lactic acid when therefore they may take higher and potentially toxic doses in metabolised anaerobically. The discrepancy between the order to hasten the weight loss effects ]. Additionally, stimulation of glycolysis and the inhibition of oxidative there have been a number of recent fatalities due to phosphorylation results in a rapid rise in the production of intentional ingestion of DNP as suicide attempts .
pyruvic acid, leading to an increased production of lacticacid [, Potential Mechanisms of Toxicity Potassium and Phosphate Accumulation The classic symptom complex observed by overdose of Mudge showed that potassium accumulates in rabbit kidney phenol-based products such as DNP is a combination of slices as the concentration of dinitrophenol is increased hyperthermia, tachycardia, diaphoresis and tachypnoea ]. The accumulation of potassium continues even after ]. There are thought to be several physiological cellular respiration is inhibited ] and hyperkalaemia has mechanisms involved in the development of toxicity of contributed to toxicity [Due to the uncoupling of DNP, which are summarised below.
oxidative phosphorylation, inorganic phosphate is no longerabsorbed into the mitochondria and accumulation takes Uncoupling of Oxidative Phosphorylation place, but whether this contributes to the clinical presenta-tion is unknown , ].
DNP decreases the formation of high-energy phosphate bondsin mitochondria and at the same time stimulates systemic Teratogenicity, Carcinogenicity and Other Toxicity oxygen consumption . This dissociative effect is knownas uncoupling of oxidative phosphorylation. Adenosine In animal studies, DNP has been shown to be teratogenic, triphosphate (ATP) production is the final product of the mutagenic and carcinogenic; developmental and reproductive tricarboxylic acid (Krebs) cycle in mitocondria along with toxicity has also been reported .
CO2 and H2O. During glycolysis, there is a net production oftwo ATP molecules, but the majority of energy-richphosphate bonds (38 in total) are produced during the final Clinical Features of DNP Toxicity oxidative phosphorylation process. During this final phase,ATP synthetase converts adenosinediphosphate to ATP with Routes of Exposure the addition of an inorganic phosphate molecule. DNPinterferes with the final energy production pathway by The oral route is currently the most common route of preventing the uptake of inorganic phosphate molecules into therapeutic and suicidal exposure. Dermal exposure can cause the mitochondria [, This results in the inhibition of all yellow staining and may have mild corrosive effects on the energy-requiring processes and the extra-mitochondrial skin. Absorption through the skin may lead to systemic effects accumulation of inorganic phosphate [DNP also acts similar to those seen following ingestion of DNP, although as a chemical ionophore, stopping the final energy conver- only mild symptoms are usually experienced. Exposure to the sion by exporting the proton ions (H+) needed for ATP eyes may cause yellow discoloration of the sclera with production across the mitochondrial membrane by increasing conjunctival injection and irritation. Dermal exposure is the the basal leak of protons ]. This shift in the proton most common route of unintentional exposure . DNP is electrochemical gradient then results in potential energy used in the chemical industry in wood preservatives, dissipating as heat, instead of being converted to ATP, with herbicides and dyes and may leak onto industrial sites rapid consumption of calories [, The heat production through landfill and storage tanks. Accidental spills during represents a failure in thermoregulatory homeostasis, leading manufacture and transport are possible and exposure is to uncontrolled hyperthermia usually through exposure to the water or dirt that it hasleaked on. Although there have been no reports of this Stimulation of Glycolysis occurring, there have been two fatalities related toindividuals recycling nylon bags that had previously El-Guindy et al. concluded that dinitrophenol produces its contained DNP . Inhalational exposure can happen by glycolytic effect through its effect on the muscle contraction breathing contaminated air at DNP-containing waste sites process . Carbohydrate consumption markedly or from incineration fumes. Inhalation of DNP fumes may increases in the presence of dinitrophenol which allows lead to significant systemic effects, similar to those seen for rapid weight loss when dinitrophenol is taken in small with ingestion.
J. Med. Toxicol. (2011) 7:205–212 Organ Systems Affected by Therapeutic Use DNP-Related Fatalities There is a small margin between the beneficial effects and Fatalities from the intake of DNP, whether accidental or the toxic effects of DNP. The most common side effect suicidal, have been reported since the turn of the twentieth reported with the therapeutic use of DNP is a rash [, – century (Table To date, there have been 62 published This rash can be maculo-papular, urticarial, angio- deaths attributed to DNP (Fig. The largest publication of oedematous or a severe exfoliative dermatitis .
36 deaths due to DNP was published in 1919 [This was There is often accompanying pruritis and subsequent a study into the deaths in munition factories in Paris due to desquamation , ]. Prolonged peripheral neuritis occupational exposure to DNP. It highlights the improve- has been reported, often affecting the hands and feet and ments made in the factory to prevent further deaths associated with skin changes [, A common through simple measures such as ventilation, personal complaint is that of yellow discoloration of the skin, sclera protective equipment and better hygiene. This combined and urine –This same yellow discoloration is often with changes in legislation brought the death rate down seen at autopsy and has been confused with jaundice due to from 16.3 per 10,000 t of DNP handled/produced to 1.2 reports of liver damage [, ].
per 10,000 t.
T wave and ST segment abnormalities have been noted During the 1930s, reported DNP-related fatalities were and some of the earlier autopsied case reports recorded all individuals who had taken it for weight loss [ heart muscle damage . Gastroenteritis and , , ]. After the 1930s, there have only been anorexia have been reported in high doses , ]. Acute two fatalities in the remainder of the twentieth century kidney injury, as evidenced by acute tubular necrosis, has , One related to deliberate ingestion of DNP [ been found at autopsy and also reported in two other cases and the other was where an individual accidentally ingested , ]. Confusion, agitation, convulsion and coma are a liquid he thought to be grape juice, but in fact contained the most common neurological effects reported , ].
derivatives of DNP [This further decline in fatalities Agranulocytosis and neutropaenia have been associated may reflect the labelling of DNP as ‘extremely dangerous with the therapeutic use of DNP [, –].
and not fit for human consumption' by the US Food and Cataracts can develop quickly after the use of DNP, usually Drug Administration in 1938.
leading to a permanent decrease in vision to light–dark Over the last decade, from 2001 to 2010, there have perception in days to months [–]. Permanent deafness been 12 deaths related to exposure to DNP. These has been reported at doses considered to be therapeutic .
fatalities have been linked to deliberate overdose , accidental toxicity associated with use by body- Intentional Overdose builders or for weight loss and accidentaloccupational exposure This resurgence in reported The average time to presentation in the reported cases of acute fatalities may reflect the increased availability of DNP or suicidal overdose is 7–8 h and the average time of death is over the internet, marketed particularly towards body- 14 h [, –]. The onset of symptoms was reported as early as 3 h and 30 min after the overdose .
Preceding death, the patient is often profoundly hyper- The usual complaint of the patient is that of profuse sweating thermic and there may be associated methaemoglobinae- The initial fever is not associated with a change in heart mia. Death is usually secondary to massive cardiovascular rate or blood pressure, but tachycardia, tachypnoea, shock, collapse. There have been frequent reports of a rapid confusion, convulsions, cardiovascular collapse and pulse- (within minutes) onset of generalised rigidity after death less electrical activity are the eventual consequence of the ]. This profound muscle rigidity has also been seen to fatal, deliberate overdose, regardless of treatment happen before death making mechanical ventilation very , However, there has been at least one case of difficult [This early onset of generalised rigidity after survival following deliberate overdose in an 18-year-old death has been attributed to the release of calcium from the female who developed typical features of DNP toxicity cytosol due to the depletion of ATP [ [tachycardia of 144 beats per minute, tachypnoea of 38–40 Ingestion is currently the most common route of breaths per minute and hyperthermia of 39.7°C (103.4°F)] exposure to the drug leading to death. The lowest She was managed conservatively with intravenous published lethal human oral dose of DNP is 4.3 mg/kg fluids and ice packs to maintain her temperature below 38.3° ]; the doses reported in the published acute and suicidal C (101°F) and was discharged less than 48 h following fatalities range from 2.8 g to an estimated 5 g. The highest admission to hospital with no adverse effects at the time of reported dose taken in acute overdose associated with discharge. Ingestion of DNP was confirmed by analysis of survival was a woman who took 2.4 g with no complications gastric lavage contents.
J. Med. Toxicol. (2011) 7:205–212 Options for Management monary resuscitation was performed in some of the cases ofDNP overdose and in one case for up to an hour ], but has There is no specific antidote for DNP poisoning and all never led to a return of spontaneous circulation. Halothane management strategies are based on case reports and expert should be avoided as possible synergistic hyperthermia may opinions, but the key to the management of DNP poisoning cause deterioration and death lies in early recognition and a high index of suspicion ].
Methaemoglobinaemia should always be suspected and Patients who have acutely overdosed on DNP in any form tested for. Levels exceeding 30% should be treated with should be observed for at least 12 h, as no patient has been intravenous methylthioninium chloride (methylene blue), recorded to be asymptomatic beyond 10 h after an acute but treatment may be started at lower serum methaemoglobin overdose During this time, their body temperature, levels in the presence of other signs of shock and tissue cardiac rhythm, heart rate and oxygen saturation should be The use of continuous veno-venous haemofiltration Although there are no previous reports of its use, in line (CVVH) has been recommended to manage hyperkalaemia with the previously published American Academy of and hyperthermia associated with DNP overdose [, Clinical Toxicology/European Association of Poisons However, there are no published cases in which CVVH or Centres and Clinical Toxciologists position statements on the similar therapies have been used in DNP poisoning.
use of oral activated charcoal, we would recommend Propranolol has been studied in dogs poisoned by DNP consideration of a single dose of activated charcoal in those and a significant reduction in lactate levels was recorded individuals who present within an hour of ingestion. Previous ], but its clinical use in humans cannot be recommended autopsies have reported a yellow coloured fluid in the due to the inhibitory effect on glucose production and intestines of some cases; there is no evidence that this fluid unknown effect on mortality. High-dose insulin and glucose contains DNP rather than staining following ingestion.
may have a beneficial effect through facilitation of glycolysis, Therefore, at this time although there is no evidence to but there is no animal or human data to support this treatment support the use of multi-dose activated charcoal and/or whole modality at this time However, glucose administration bowel irrigation, we feel that the potential benefit outweighs alone may be useful since glycolysis would be the main the potential risk. External decontamination, if appropriate, source of ATP production in DNP-poisoned cells .
should be undertaken by washing to reduce dermal exposure.
Based on the underlying pathophysiological principles andprevious experience, it would be advisable to avoid the use of salicylates as it may worsen the DNP-relatedtoxidrome Aggressive fluid resuscitation should be DNP has been available for over a century, initially in the initiated, using cooled fluids in those with hyperthermia.
manufacture of munitions, due to its explosive properties.
Seizures should be controlled with benzodiazepines. These From the 1930s onwards, there has been interest in its may also be needed to control severely agitated patients, as properties to increase the underlying metabolic rate, leading their agitation will add to the hyperthermic state which may to an associated weight loss. Following a number of deaths lead to circulatory collapse. External cooling measures with in the 1930s, the US Food and Drug Administration ice or cooling blankets should be initiated to control determined that DNP was ‘extremely dangerous and not hyperpyrexia , If benzodiazepines do not fit for human consumption'. There were very few reported control agitation or seizures, then paralysis, intubation and deaths since the late 1930s, until the last decade. It appears ventilation should be considered. Dantrolene and ice baths that there has been increasing interest and availability of have been used to control the severe hyperthermic state DNP-containing products on the internet. Whilst these There is the possibility for the use of external appear to be largely targeted towards bodybuilders to try cooling devices, such as those used to induce therapeutic and reduce fat and improve muscle bulk, there have been a hypothermia following an out of hospital cardiac arrest, to number of deaths related to its use for more general weight rapidly reduce temperature; however, there have been no loss. The primary toxicity seen with DNP is similar to that previous reports of using these devices in patients with DNP seen with other phenol-based products and is a combination toxicity. Dantrolene has previously been recommended to of hyperthermia, tachycardia, diaphoresis and tachypnoea manage the hyperthermia associated with the use of DNP.
with associated cardiovascular collapse/cardiac arrest and There is no evidence to support this recommendation, but it death. There is no specific management for individuals with has been used successfully in a single case report [, DNP-related toxicity; it is imperative that the temperature is Intravenous vasopressors and/or inotropes should be brought down as rapidly and as soon as possible to try and considered accompanied with invasive arterial monitoring if reduce systemic toxicity and/or death. Currently, DNP fluid therapy fails to maintain the blood pressure. Cardiopul- remains freely available on the internet, with both detailed J. Med. Toxicol. (2011) 7:205–212 ‘regimens' for its use and about the potential for acute toxicity 20. Author unknown. Death after slimming treatment. The Lancet and death on the internet seller websites. It is likely that 21. Tewari A, Ali A, O'Donnell A, Butt MS (2009) Weight loss and some individuals, despite these warnings, will continue to 2,4-dinitrophenol poisoning. Br J Anaesth 102:566–567 purchase and use DNP-containing products to aid with weight 22. Siegmueller C, Narasimhaiah R (2010) Fatal 2,4-dinitrophenol loss, with the potential risk of acute toxicity and/or death.
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