2,4-Dinitrophenol (DNP) Profile

[Cyber]

2,4-Dinitrophenol (DNP), C6H4N2O5, is a cellular metabolic poison. It uncouples oxidative phosphorylation by carrying protons across the mitochondrial membrane, leading to a rapid consumption of energy without generation of ATP.
Dinitrophenols as a class of compounds, of which there are six members, do not occur naturally but are all manufactured compounds.
2,4-Dinitrophenol


Identifiers
CAS number 51-28-5 YesY
PubChem 1493
ChemSpider 1448
UN number 0076, 1320
SMILES
InChI
InChI key UFBJCMHMOXMLKC-UHFFFAOYAV
Properties
Molecular formula C6H4N2O5
Molar mass 184.106
Density 1.683 g/cm³
Melting point 108 °C, 381 K, 226 °F
Boiling point 113 °C, 386 K, 235 °F
Acidity (pKa) 4.114

Hazards
R-phrases R10 R23 R24 R25 R33
S-phrases (S1) (S2) S28 S37 S45
Chemical properties
2,4-Dinitrophenol is a yellow, crystalline solid that has a sweet, musty odor. It sublimes when carefully heated and is volatile with steam. It is soluble in water (sparingly) (its crystalline sodium salts are also soluble in water), cold water (sparingly), ethyl acetate, acetone, chloroform, pyridine, carbon tetrachloride, toluene, alcohol, benzene, and aqueous alkaline solutions (Merck, 1989). It forms explosive salts with alkalies and ammonia, and emits toxic fumes of nitrogen oxides when heated to decomposition (Sax, 1989). It is incompatible with heavy metals and their compounds.
Uses
Commercial DNP is primarily used for scientific research and in manufacturing. It has been used at times to make dyes, other organic chemicals, and wood preservatives. It has also been used to make photographic developer, explosives, and pesticides.
Pharmacological action
In living cells, DNP acts as a proton ionophore, an agent that can shuttle protons (hydrogen ions) across biological membranes. It defeats 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.
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. 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. 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’s 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 meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation. The production or “phosphorylation” of ATP by ATP synthase gets disconnected or “uncoupled” from oxidation. Interestingly, 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. In light of this, it’s advised that the dose be slowly titrated according to personal tolerance, which varies greatly. Case reports have shown that an acute administration of 20–50 mg/kg in humans can be lethal. Concerns about dangerous side-effects and rapidly developing cataracts 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 are rare, but are still reported on occasion. These include cases of accidental exposure, suicide, and excessive intentional exposure.
There are limited and conflicting data on the pharmacokinetics of DNP in humans. The EPA states that “Data on the elimination kinetics of the dinitrophenols or their metabolic products in humans were not found.” 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.” 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.” Oddly, more recent papers give an 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.
Although further investigation is needed, dinitrophenol-induced hyperthermia has been successfully resolved with dantrolene administration.”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.”
While DNP itself is considered by many to be too risky for human use, its mechanism of action remains under investigation as a potential approach for treating obesity. Currently, research is being conducted on uncoupling proteins naturally found in humans.
Environmental toxicity
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 there is anaerobic toxicity due to a reduced methane production.