Dinitrophenol action

Dinitrophenol is an expl less powerful and brisant, and less sensitive to mechanical action than TNT, but more sensitive than DNB or DNT. Some of its expl props were detd in Ger by Will (Ref 2) and Wohler (Ref 4), in Fr by Burlot (Ref 6), and in the USA by the Ordnance Dept (Ref 9) ... 

The action of uncouplers is to dissociate oxidation in the respiratory chain from phosphorylation. These compounds are toxic in vivo, causing respiration to become uncontrolled, since the rate is no longer limited by the concentration of ADP or Pj. The uncoupler that has been used most frequently is 2,4-dinitrophenol, but other compounds act in a similar manner. The antibiotic oligomycin completely blocks oxidation and phosphorylation by acting on a step in phosphorylation (Figures 12-7 and 12-8). 

Dinitrophenol is a member of the aromatic family of pesticides, many of which exhibit insecticide and fungicide activity. DNP is considered to be highly toxic to humans, with a lethal oral dose of 14 to 43mg/kg. Environmental exposure to DNP occurs primarily from pesticide runoff to water. DNP is used as a pesticide, wood preservative, and in the manufacture of dyes. DNP is an uncoupler, or has the ability to separate the flow of electrons and the pumping of ions for ATP synthesis. This means that the energy from electron transfer cannot be used for ATP synthesis [75,77]. The mechanism of action of DNP is believed to inhibit the formation of ATP by uncoupling oxidative phosphorylation. 

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

Polarographic studies of a mitochondrial fraction from Hymenolepis diminuta showed that of four substrates tested, DL-glycerol-3-phosphate was the most rapidly oxidized, but the highest respiratory control ratio (1.7) was obtained with dl-isocitric acid. With isocitrate as substrate oxyclozanide at 1.61 nM stimulated O uptake and relieved oligomycin inhibition of adinosine diphosphate-stimulated respiration, but at concentrations above 2 pM progressively inhibited O uptake. Rafoxanide, niclosamide, 3,4,5-tribromo-salicylanilide, nitroxynil, resorantel, di-chlorophen, and 2,4-dinitrophenol exhibited effects similar to those of oxyclozanide on the respiration in cestode mitochondria. The relative potencies were compared and the possible mode of action discussed [38]. 

Sophisticated isotope experiments were also performed using H2180 (Mildred Cohn) and 32P, and various exchange reactions identified between ATP, ADP, and Pr Analysis of the mode of action of two inhibitors was also relevant. Dinitrophenol (DNP) uncoupled the association between oxidation and ATP generation (Lardy and Elvejhem, 1945 Loomis and Lipmann, 1948). Oligomycin inhibited reaction (ii) above, blocking the terminal phosphorylation to give ATP, but not apparently the formation of A C. 

Morley GE, Anumonwo JMB, Delmar M Effects of 2,4-dinitrophenol or low [ATP on cell excitability and action potential propagation in guinea pig ventricular myocytes. Circ Res 1992 71 821-830. 

Dinitrophenols had been used as insecticides since 1892 but it was not until the 1930s that their value as herbicides was discovered and 4,6-dinitro-o-cresol (DNOC) was introduced. The trouble with dinitrophenols was their toxicity to all living organisms that respire. Their mode of action is through the uncoupling of oxidative phosphorylation, an effect that leads to a rapid death of any organism that comes into contact with the chemical, including the operator. 

Amino-4-nitrophenol has been prepared by the partial reduction of 2,4-dinitrophenol chemically -6 and electrolytically,6 and by the action of sulfuric add on 3-nitroazidobenzene.7... 

Fetterer, R.H., Pax, R.A. and Bennett, J.L. (1980) Praziquantel, potassium and 2,4-dinitrophenol analysis of their action on the musculature of Schistosoma mansoni. European Journal of Pharmacology 64, 31-38. 

Sulfur Black T is produced by boiling 2,4-dinitrophenol with sodium polysulfide and is presumably a phenothiazonethianthrene macromolecule. The water-insoluble forms of these dyes can be treated with various reducing agents to yield the water-soluble leuco sulfur dyes, which are fairly unstable. More stable water-solubilized sulfur dyes can be obtained by the action of sodium sulfite or bisulfite... 

The action of nitric acid on diacetylated p-aminophenol yields a dinitro derivative for which four structures are possible. Hydrolysis followed by deamination gives the known 3,5-dinitrophenol, thus proving that substitution occurs ortho to the acylated amino group.141... 

Mode of Action of Dicyclohexylcarbodiimide (DCCD) When DCCD is added to a suspension of tightly coupled, actively respiring mitochondria, the rate of electron transfer (measured by 02 consumption) and the rate of ATP production dramatically decrease. If a solution of 2,4-dinitrophenol is now added to the preparation, 02 consumption returns to normal but ATP production remains inhibited. 

Chemical properties. A chlorine atom ortho or para to a nitro group is especially reactive and is readily substituted. Numerous examples of such reactions, utilized in the preparation of explosives, are given later in the descriptions of preparation methods for dinitrophenol, dinitroanisole, hexanitrodiphenylamine, hexanitro-diphenyl sulphone, dinitroaniline, tetryl, etc. Chlorodinitrobenzene reacts with sodium sulphide and sulphur to yield sulphur dyes. The action of sodium disulphide results in the formation of tetranitrodiphenyl sulphide (p. 554). 

The B group colicins are believed to act by blocking the energy metabolism of the cell. Accordingly, the siderophores were tested for ability to block the action of the poisons azide, 2,4-dinitrophenol, or CCCP no protection was found. 

Williamson and Metcalf 1967). In one study, the uncoupling action of DNOC and other dinitrophenol derivatives were investigated as well as the relationship between their uncoupling potency and toxicity (llivicky and Casida 1969). Mitochondria from mouse liver and brain were equally sensitive to the uncoupling action of DNOC. Isolated brain and liver mitochondria from mice treated with dinitrophenols derivatives other than DNOC were completely uncoupled or inhibited only when the dose resulted in severe symptoms of poisoning (llivicky and Casida 1969). DNOC was not tested in this experiment, but the data from these studies suggest that a relationship between the severity of DNOC toxicity and the extent of uncoupling by DNOC may exist. 

Gold and Rochester (S4] and Johnson and Rees [55] described a transformation of 13iS-trinitrobenzene into 3,S dinitrophenol under photochemical action of OH [compare with reaction (11) in Vol. I, p. 251 ]. 

A heterolytic substitution of l-methoxy-3.5 dinitrobenzene througli the action of ultraviolet light was described by llavinga and co-workers [57]. 3,5-Dinitrophenol resulted, i.e. demethylation occurred. 

These experts collectively have knowledge of dinitrophenol s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. 

Cutting WC, Mehrtens HG, Tainter ML. 1933. Actions and uses of dinitrophenol. JAMA 101 193-195. 

Cutting WC, Tainter ML. 1933. Metabolic actions of dinitrophenols with the use of balanced and unbalanced diets. JAMA 27 2099-2102. 

Masserman JH, Goldsmith H. 1934. Dinitrophenol Its therapeutic and toxic actions in certain types of psychobiologic underactivity. JAMA 102 523-525. 

Tainter ML, Cutting WC. 1933a. Febrile, respiratory and some other actions of dinitrophenol. J Pharmacol Exp Ther 48 410-429. 

TainterML, Cutting WC. 1933b. Miscellaneous actions of dinitrophenol. Repeated administrations, antidotes, fatal doses, antiseptic tests and actions of some isomers. J Pharmacol Exp Ther 49 187-209. 

Other potential antagonists of BoNT action such as elevated calcium, calcium ionophores, lanthanum, black widow spider venom, 2,4-dinitrophenol, and agents that raise cyclic AMP levels... 

Pesticides with this mode of action include such old products as the dinitrophenols (dinitroorthocreosol [DNOC], dinoterb, and dinoseb) and other phenols such as pentachlorophenol and ioxynil. DNOC is a biocide useful against mites, insects, weeds, and fungi. The mammalian toxicity is rather high, with a rat oral LD50 (lethal dose in 50% of the population) of 25 to 40 mg/kg of the sodium salt. The typical symptom is fever, which is... 

Because so few Na and Ions move across the plasma membrane during each action potential, the Na /K pump that maintains the usual Ion gradients plays no direct role In Impulse conduction. When this pump Is experimentally Inhibited by dinitrophenol or another Inhibitor of ATP production, the concentrations of Na and... 

The fungitoxic effect of phenols can be increased by the introduction of nitro groups. Even the introduction of a single nitro group strengthens the antifungal action, but dinitrophenols have been applied most widely as fungicides. Dinitro-... 

The mode of action of dinitrophenols is that free dinitroalkylphenols liberated in the organism inhibit oxidative phosphorylation. In this group of compounds the biological action is connected with the biochemical reducibility of the nitro group and, in this respect, species-specific differences can be observed between different organisms (Josepovits, 1966). 

Researches have investigated the biological action of other alkyl-dinitrophenols as a function of the structure of the compounds (Byrde et al., 1969 Clifford et ai, 1969 and 1972). 

According to Simon (1953) five different mechanisms can be distinguished by which dinitrophenols affect the living cells. These include oxidative phosphorylation and photosynthetic phosphorylation which are considered as their main effects. Dinitrophenols in addition affect glycolytic phosphorylation, respiration and fermentation reaction. General other observed effects are protein denaturation and their inhibiting action on lipid synthesis, RNA and protein synthesis. 

---