2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimes, is volatile with steam, and is soluble in most organic solvents as well as aqueous alkaline solutions. When in a dry form, it's a high explosive and has an instantaneous explosion hazard. It is a precursor to other chemicals and is biochemically active, inhibiting adenosine triphosphate (ATP) production in cells with mitochondria. Its use in high doses as a dieting aid has been identified with severe side-effects, including a number of deaths.
Commercial DNP is used as an antiseptic and as a non-selective bioaccumulating pesticide.
DNP is particularly used as a herbicide alongside with other closely related dinitrophenol herbicides like 2,4-dinitro-o-cresol (DNOC), dinoseb and dinoterb. Since 1998 DNP was withdrawn from agriculture use. Currently there is no actively registered pesticides containing DNP in US or Europe.
Although DNP is widely considered too dangerous for clinical use, its mechanism of action remains under investigation as a potential approach for treating obesity. As of 2015, research is being conducted on uncoupling proteins naturally found in humans.
In living cells, DNP acts as a proton ionophore, an agent that can shuttle protons (hydrogen cations) across biological membranes. It dissipates the proton gradient across mitochondria and chloroplast membranes, collapsing the proton motive force that the cell uses to produce most of its ATP chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as heat.
DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and to meet energy demands. DNP is probably the best known agent for uncouplingoxidative phosphorylation. The "phosphorylation" of adenosine diphosphate (ADP) by ATP synthase gets disconnected or "uncoupled" from oxidation.
"Dinitrophenol uncouples oxidative phosphorylation, causes release of calcium from mitochondrial stores and prevents calcium re-uptake. This leads to free intracellular calcium and causes muscle contraction and hyperthermia. Dantrolene inhibits calcium release from the sarcoplasmic reticulum which reduces intracellular calcium. The resulting muscle relaxation allows heat dissipation. There is little risk to dantrolene administration. Since dantrolene may be effective in reducing hyperthermia caused by agents that inhibit oxidative phosphorylation, early administration may improve outcome."
Information about pharmacokinetics of DNP in humans is limited. The ATSDR's Toxicological Profile for Dinitrophenols remarks that DNP elimination appears to be rapid except when liver function is impaired. The NEJM remarks that DNP appears to be eliminated in around three to four days, except possibly when the liver and kidneys are damaged. Other papers give a wide array of possible half-lives, ranging from 3 hours, to 5–14 days. Other recent papers maintain that the half-life in humans is unknown.
DNP is considered to have high acute toxicity. Acute oral exposure to DNP has resulted in increased basal metabolic rate, nausea, vomiting, sweating, dizziness, headache, and loss of weight. Chronic oral exposure to DNP can lead to the formation of cataracts and skin lesions and has caused effects on the bone marrow, central nervous system, and cardiovascular system. Contact with skin or inhalation can cause DNP poisoning. In 2009, an incident occurred in a Chinese chemical factory and 20 persons suffered acute DNP poisoning.
The factor that limits ever-increasing doses of DNP is not a lack of ATP energy production, but rather an excessive rise in body temperature due to the heat produced during uncoupling. Accordingly, DNP overdose will cause fatal hyperthermia, with body temperature rising to as high as 43.1 °C (109.6 °F) shortly before death. Case reports have shown that an acute administration of 10–20 mg per kilogram of body weight in humans can be lethal. The lowest published fatal ingested dose is 4.3 mg/kg. One dose, as few as two tablets have proved fatal.
The United Kingdom's Food Standards Agency identifies DNP as "an industrial chemical known to have serious short-term and long-term effects, which can be extremely dangerous to human health." and advises "consumers not to take any product containing DNP at any level. This chemical is not suitable for human consumption." From December 2018 DNP has been classified as an "illegal poisonous substance" in Russia.
DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on how the compound substantially increased metabolic rate. This effect occurs via DNP acting as a proton ionophore. After only its first year on the market, Tainter estimated that at least 100,000 people had been treated with DNP in the United States, in addition to many others abroad.
In light of the adverse effects and fatal hyperthermia caused by DNP when it was used clinically, the dose was slowly titrated according to personal tolerance, which varies greatly. Concerns about dangerous side-effects and rapidly developing cataracts resulted in DNP being discontinued in the United States by the end of 1938.
"In studies of intermediate-duration oral exposure to 2,4-DNP, cases of death from agranulocytosis (described in the discussion of Hematological Effects) have been attributed to 2,4-DNP. These cases occurred during the usual dosing regimens for weight loss, employing increasing doses in one case from 2.9 to 4.3 mg/kg/day of 2,4-DNP for 6 weeks (Dameshek and Gargill 1934); a dose of 1.03 mg/kg/day 2,4-DNP for 46 days in another case (Goldman and Haber 1936); and in another, from 0.62 to 3.8 mg/kg/day 2,4-DNP as sodium 2,4-DNP for 41 days (Silver 1934). In all cases, the patients were under medical supervision."
DNP, however, continues to be used by some bodybuilders and athletes to rapidly lose body fat. Fatal overdoses include cases of accidental exposure, suicide, and excessive intentional exposure (overdose). The substance's use as a dieting aid has also led to a number of accidental fatalities, including 26 confirmed DNP-related deaths in UK since 2007. Annual Reports of the American Association of Poison Control Centers identifies 15 DNP poisoning fatalities between 2013 and 2017 in US. Swedish Poisons Information Centre has reported three fatal DNP cases between June 2012 and May 2013. “Forensic analysis of DNP is not routinely performed so the true number of DNP deaths may be higher.” DNP may not be detected in post mortem blood samples.
In 2003, a vendor of DNP was sentenced to prison for mail fraud, with the FDA's OCI investigators having gathered evidence that the vendor's encapsulation of DNP was neither accurate nor sanitary. In 2018, a seller in United Kingdom was convicted of manslaughter for selling DNP as "fatburner" for human consumption. In 2019, a company selling DNP in the UK was found "guilty of placing an unsafe food product on to the market" and fined £100,000. Director of the company was given suspended prison sentence. The seller in California was sentenced to three years in prison for selling DNP as a diet pills.
^Barker K, Seger D, Kumar S (2006). "Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'"". Clin Toxicol. 44 (3): 351. doi:10.1080/15563650600584709. PMID16749560.
^Korde AS, Pettigrew LC, Craddock SD, Maragos WF (September 2005). "The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia". J. Neurochem. 94 (6): 1676–1684. doi:10.1111/j.1471-4159.2005.03328.x. PMID16045446.
^ abcHsiao AL, Santucci KA, Seo-Mayer P, et al. (2005). "Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a "dietary supplement"". Clin Toxicol. 43 (4): 281–285. doi:10.1081/clt-200058946. PMID16035205.
^ abcA. Hahn, K. Begemann, R. Burger, J. Hillebrand, H. Meyer, K. Preußner: "Cases of Poisoning Reported by Physicians in 2006", page 40. BfR Press and Public Relations Office, 2006.
^Public Health Service, U.S. Department of Health and Human Services (1995). "Toxicological Profile for Dinitrophenols". Agency for Toxic Substances and Disease Registry. Cite journal requires |journal= (help)
^Khabarov, Yu. G.; Lakhmanov, D. E.; Kosyakov, D. S.; Ul’yanovskii, N. V. (1 October 2012). "Synthesis of 2,4-dinitrophenol". Russian Journal of Applied Chemistry. 85 (10): 1577–1580. doi:10.1134/S1070427212100163. ISSN1608-3296.
^Bartlett J, Brunner M, Gough K (February 2010). "Deliberate poisoning with dinitrophenol (DNP): an unlicensed weight loss pill". Emerg Med J. 27 (2): 159–160. doi:10.1136/emj.2008.069401. PMID20156878.
^ abMcFee RB, Caraccio TR, McGuigan MA, Reynolds SA, Bellanger P (2004). "Dying to be thin: a dinitrophenol related fatality". Veterinary and Human Toxicology. 46 (5): 251–254. PMID15487646.
^Miranda EJ, McIntyre IM, Parker DR, Gary RD, Logan BK (2006). "Two deaths attributed to the use of 2,4-dinitrophenol". Journal of Analytical Toxicology. 30 (3): 219–222. doi:10.1093/jat/30.3.219. PMID16803658.
^Campos, Eduardo Geraldo de; Fogarty, Melissa; Martinis, Bruno Spinosa De; Logan, Barry Kerr (2019). "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". Journal of Forensic Sciences. 0. doi:10.1111/1556-4029.14154. ISSN1556-4029. PMID31430392.