2,4-Dinitrophenol

2,4-Dinitrophenol
Names
IUPAC name
2,4-dinitrophenol
Other names
Solfo Black
Identifiers
51-28-5 YesY
3D model (Jmol) Interactive image
Interactive image
ChEBI CHEBI:42017 YesY
ChEMBL ChEMBL273386 YesY
ChemSpider 1448 YesY
DrugBank DB04528 YesY
ECHA InfoCard 100.000.080
KEGG C02496 YesY
PubChem 1493
UNII Q13SKS21MN YesY
UN number 0076, 1320
Properties
C6H4N2O5
Molar mass 184.11 g·mol−1
Density 1.683 g/cm3
Melting point 108 °C (226 °F; 381 K)
Boiling point 113 °C (235 °F; 386 K)
Acidity (pKa) 4.114
Hazards
R-phrases R10 R23 R24 R25 R33
S-phrases (S1) (S2) S28 S37 S45
NFPA 704
Flammability code 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g., gasoline) Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 3: Capable of detonation or explosive decomposition but requires a strong initiating source, must be heated under confinement before initiation, reacts explosively with water, or will detonate if severely shocked. E.g., fluorine Special hazards (white): no codeNFPA 704 four-colored diamond
3
3
3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

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.[1] It is a precursor to other chemicals and is biochemically active, inhibiting energy (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.[2]

Synthesis

DNP is produced by hydrolysis of 2,4-dinitrochlorobenzene.[3]

Uses

Commercial DNP is used as an antiseptic and as a pesticide.[4] It is a chemical intermediate in the production of sulfur dyes,[3] wood preservatives,[4] and some herbicides including dinoseb and dinoterb. DNP has also been used to make photographic developers and explosives.

Biochemical aspects

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 is often used in biochemistry research to help explore the bioenergetics of chemiosmotic and other membrane transport processes.

Health effects

DNP is considered to have high acute toxicity.[4] Acute oral exposure to DNP has resulted in increased basal metabolic rate, nausea, vomiting, sweating, dizziness, headache, and loss of weight.[4] 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.[4][5]

Dieting aid

DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on the drug's ability to greatly increase metabolic rate.[6][7] After only its first year on the market Tainter estimated that probably at least 100,000 persons had been treated with DNP in the United States, in addition to many others abroad.[8] 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 uncoupling oxidative phosphorylation. The "phosphorylation" of adenosine diphosphate (ADP) by ATP synthase gets disconnected or "uncoupled" from oxidation.

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 44 °C (111 °F) shortly before death. In light of this, when it was used clinically, the dose was slowly titrated according to personal tolerance, which varies greatly.[9]

Case reports have shown that an acute administration of 20–50 mg per kilogram of body weight in humans can be lethal.[10] Concerns about dangerous side-effects and rapidly developing cataracts[11] resulted in DNP being discontinued in the United States by the end of 1938. DNP, however, continues to be used by some bodybuilders and athletes to rapidly lose body fat. Fatal overdoses include cases of accidental exposure,[12] suicide,[10][13][14] and excessive intentional exposure (overdose).[13][15][16] The substance's use as a dieting aid has also led to a number of accidental fatalities.[17][18][19][20]

Although DNP is widely considered too dangerous for clinical use due to its numerous potential side effects, such as cataracts,[21] its mechanism of action remains under investigation as a potential approach for treating obesity.[22] Currently, research is being conducted on uncoupling proteins naturally found in humans.

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."[23]

Pharmacokinetics

Information about pharmacokinetics of DNP in humans is limited and conflicting. The EPA states that "Data on the elimination kinetics of the dinitrophenols or their metabolic products in humans were not found."[24] The ATSDR's Toxicological Profile for Dinitrophenols also states that "No studies were located regarding distribution in humans after oral exposure to 2,4-DNP. Limited information is available regarding distribution in animals after oral exposure to 2,4-DNP." However, they do state that "Elimination from the body appears to be rapid, except possibly in cases of compromised liver function."[25] This coincides with a review in the NEJM on the biological actions of dinitrophenol, which stated that "Judging from the metabolic response, DNP appears to be eliminated entirely in three or four days; in the presence of liver or kidney damage it is possible that the drug will be retained over a longer period."[26] Oddly, more recent papers give an array of possible half-lives, ranging from 3 hours,[27] to 5–14 days.[10] Other recent papers maintain that the half-life in humans is unknown.[13]

Although further investigation is needed, one case report notes that dinitrophenol-induced hyperthermia has been successfully resolved with dantrolene administration.[28] "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."[29]

Commerce

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.[30]

Environmental effects

DNP is considered an important environmental contaminant by the United States Environmental Protection Agency. It has been found in 61 of 1400 priority sites that need clean-up of industrial waste. It can enter the air from automobile exhaust, burning of certain industrial substances, and from reaction of nitrogen in air with other atmospheric chemicals. The major site of degradation is the soil, where microorganisms metabolize it.

However, the effects of DNP on anaerobic micro-organisms are still largely undetermined. Some studies suggest that there is anaerobic toxicity due to a reduced methane production.

DNP forms explosive salts with strong bases and ammonia, and emits toxic fumes of nitrogen dioxide when heated to decomposition.[31]

References

  1. ↑ Budavari, Susan(ed); O'Neil, Maryadele J(ed); Heckelman, Patricia E(red). "The Merck Index" Rahway, NJ; Merck & Co; 1989. [1900] p.
  2. ↑ Summary of previously published fatalities relating to exposure to DNP including basic demographics, amount of exposure and maximal temperature recorded pre-death
  3. 1 2 Gerald Booth "Nitro Compounds, Aromatic" in "Ullmann's Encyclopedia of Industrial Chemistry" 2007; Wiley-VCH, Weinheim. doi:10.1002/14356007.a17_411
  4. 1 2 3 4 5 "2,4-Dinitrophenol". Environmental Protection Agency.
  5. ↑ Public Health Service, U.S. Department of Health and Human Services (1995). "Toxicological Profile for Dinitrophenols". Agency for Toxic Substances and Disease Registry.
  6. ↑ Cutting WC, Mehrtens HG, Tainter ML (1933). "Actions and uses of dinitrophenol: Promising metabolic applications". J Am Med Assoc. 101 (3): 193–195. doi:10.1001/jama.1933.02740280013006.
  7. ↑ Tainter ML, Stockton AB, Cutting WC (1933). "Use of dinitrophenol in obesity and related conditions: a progress report". J Am Med Assoc. 101 (19): 1472–1475. doi:10.1001/jama.1933.02740440032009.
  8. ↑ Tainter ML, Cutting WC, Stockton AB (1934). "Use of Dinitrophenol in Nutritional Disorders : A Critical Survey of Clinical Results" (pdf). Am J Public Health. 24 (10): 1045–1053. doi:10.2105/AJPH.24.10.1045. PMC 1558869Freely accessible. PMID 18014064.
  9. ↑ Simkins S. (1937). "Dinitrophenol and desiccated thyroid in the treatment of obesity: a comprehensive clinical and laboratory study". J Am Med Assoc. 108: 2110–2117. doi:10.1001/jama.1937.02780250024006.
  10. 1 2 3 Hsiao AL, Santucci KA, Seo-Mayer P, et al. (2005). "Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a "dietary supplement"". Clin Toxicol (Phila). 43 (4): 281–285. doi:10.1081/clt-200058946. PMID 16035205.
  11. ↑ "A Study of Dinitrophenol and Its Relation to Cataract Formation".
  12. ↑ Leftwich RB, Floro JF, Neal RA, Wood AJ (February 1982). "Dinitrophenol poisoning: a diagnosis to consider in undiagnosed fever". South. Med. J. 75 (2): 182–184. doi:10.1097/00007611-198202000-00016. PMID 7058360. Retrieved 18 November 2008.
  13. 1 2 3 A. 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.
  14. ↑ 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. PMID 20156878.
  15. ↑ McFee 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. PMID 15487646.
  16. ↑ 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. PMID 16803658.
  17. ↑ Dying to be thin: a dinitrophenol related fatality.
  18. ↑ http://wiadomosci.onet.pl/regionalne/warszawa/dwudziestolatka-zmarla-po-kuracji-odchudzajacej-za,1,5535542,region-wiadomosc.html
  19. ↑ http://metro.co.uk/2015/04/20/mothers-heart-wrenching-warning-after-daughters-insides-explode-like-tnt-from-taking-internet-diet-pills-5159053/
  20. ↑ "Chris Mapletoft parents 'shocked' over diet pills death". BBC News. 17 September 2013.
  21. ↑ "Hyderabad millionaire's son dies after taking bodybuilding pills".
  22. ↑ Harper JA, Dickinson K, Brand MD (2001). "Mitochondrial uncoupling as a target for drug development for the treatment of obesity". Obesity Reviews. 2 (4): 255–265. doi:10.1046/j.1467-789X.2001.00043.x. PMID 12119996.
  23. ↑ "Warning about 'fat-burner' substances containing DNP". Food Standards Agency. Retrieved 23 April 2013.
  24. ↑ "Ambient water quality criteria for nitrophenols, 440/5-80-063" (PDF). U.S. Environmental Protection Agency. 1980. Retrieved 9 June 2008.
  25. ↑ Harris, M. O.; Cocoran, J. J. (1995). "Toxicological Profile for Dinitrophenols". Agency for Toxic Substances and Disease Registry. Retrieved 23 April 2013.
  26. ↑ Edsall, G. (1934). "Biological actions of dinitrophenol and related compounds: a review". The New England Journal of Medicine. 211 (9): 385–390. doi:10.1056/NEJM193408302110901.
  27. ↑ 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. PMID 16045446.
  28. ↑ Kumar S, Barker K, Seger D. Dinitrophenol-Induced Hyperthermia Resolving With Dantrolene Administration. Abstracts of the North American Congress of Clinical Toxicology. Clin Toxicol 2002; 40:599–673.
  29. ↑ Barker K, Seger D, Kumar S (2006). "Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'"". Clin Toxicol (Phila). 44 (3): 351. doi:10.1080/15563650600584709. PMID 16749560.
  30. ↑ "Office of Criminal Investigation 2003". U.S. Food and Drug Administration. U.S. Food and Drug Administration. 8 Jun 2015. Retrieved 10 Sep 2015.
  31. ↑ Sax, N.Irving; Bruce, Robert D (1989). Dangerous properties of industrial materials. 3 (7th ed.). John Wiley & Sons. ISBN 0-442-27368-1.

Further reading

External links

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