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PubMed1996

Initial hydrogenation and extensive reduction of substituted 2,4-dinitrophenols.

Rhodococcus erythropolis HL 24-1 isolated as a 2,4-dinitrophenol-degrading organism can utilize 2-chloro-4,6-dinitrophenol as the sole nitrogen, carbon, and energy source under aerobic conditions. This compound is metabolized with liberation of stoichiometric amounts of chloride and nitrite. Under anaerobic conditions, 2,4-dinitrophenol was transiently accumulated in the culture fluid, indicating a reductive elimination of chloride. During aerobic bioconversion of 2-amino-4,6-dinitrophenol by R. erythropolis HL 24-1, a reductive elimination of nitrite leading to 2-amino-6-nitrophenol was observed. Elimination of chloride or nitrite by the initial formation of a hydride Meisenheimer complex is discussed. A methyl group in the ortho position of the 2,4-dinitrophenol gives rise to an extensive reduction of the aromatic ring under aerobic conditions. Thus, 2-methyl-4,6-dinitrophenol was shown to be converted to the two diastereomers of 4,6-dinitro-2-methylhexanoate as dead-end metabolites which were identified by spectroscopic methods.

Journal Article↗

PubMed1996

Comparative effects of the metabolic inhibitors 2,4-dinitrophenol and iodoacetate on mouse neuroblastoma cells in vitro.

The toxic effects of two metabolic inhibitors, dinitrophenol and iodoacetic acid, were compared. Mouse neuroblastoma cell cultures (Neuro-2a) were exposed to different concentrations of the toxic compounds for 24, 48 and 72 h to study basal toxicity effects (cell proliferation by quantification of total protein content (PR) and relative neutral red uptake (RNRU) by lysosomes). The following biochemical indicators assessed in the in vitro test system were: cytosolic phosphofructokinase (PFK) and enolase (ENL) activities in glycolysis; mitochondrial succinate dehydrogenase (SDH) activity in the citric acid cycle; lysosomal beta-galactosidase (GAL) activity; and neuronal acetylcholinesterase (AChE) activity. The effects of the two metabolic inhibitors on the various indicators differed. Iodoacetic acid was found to be far more toxic than dinitrophenol to neuroblastoma cell proliferation at 24 h exposure. Though 2,4-dinitrophenol and iodoacetic acid both inhibited cell proliferation of the neuroblastoma cells, their effects on the other endpoints were opposite. Dinitrophenol was a general activator of the metabolism, particularly affecting lysosomal function. Iodoacetic acid did not significantly alter general metabolism, but considerably modified lysosomal function and AChE activity. The modification of lysosomal function of Neuro-2a cells by the two compounds was quite different: dinitrophenol increased RNRU and GAL activity, and iodoacetic acid decreased both parameters.

2,4-Dinitrophenol↗

PubMed1995

Octanoate affects 2,4-dinitrophenol uncoupling in intact isolated rat hepatocytes.

When intact isolated rat hepatocytes, either incubated or perifused, were uncoupled by 2,4-dinitrophenol, we found that the effect on glucose and lactate+pyruvate fluxes, cytosolic and mitochondrial redox states and ATP/ADP ratios were dependent on the nature of the exogenous substrate added. 2,4-Dinitrophenol addition (0.25 mmol/l) to cells perifused with dihydroxyacetone (10 mmol/l) resulted in a modest and transient activation of oxygen uptake accompanied by a surprising rise in lactate/pyruvate ratio indicating an increase in the cytosolic NADH/NAD+ ratio. In addition, such uncoupling, fully abolished glucose production, enhanced lactate+pyruvate flux, and strongly decreased cytosolic and mitochondrial ATP/ADP ratios. In these steady-state conditions, further addition of octanoate (0.4 mmol/l) induced a large and sustained enhancement of respiration with a concomitant decrease in the lactate/pyruvate ratio, whereas glucose flux was restored to some extent and cytosolic and mitochondrial ATP/ADP ratios increased. Inhibition of the malate-aspartate shuttle by the transaminase inhibitor aminooxyacetate (0.3 mmol/l) did not modify the effect of 2,4-dinitrophenol with dihydroxyacetone alone whereas it decreased the maximal stimulation of oxygen uptake after octanoate addition. In view of these results we propose the following conclusions. The uncoupling of intact cells by 2,4-dinitrophenol inhibits the translocation of reducing equivalents into the mitochondrial matrix probably by impairing the malate-aspartate shuttle. This explains the increase in the cytosolic NADH/NAD+ ratio and the transient activation of respiration with dihydroxyacetone. Fatty acid addition to cells uncoupled with 2,4-dinitrophenol appears to restore a mitochondrial membrane potential, probably by providing the respiratory chain with reduced cofactors directly in the matrix, thus allowing the transfer of reducing equivalents across the mitochondrial membrane. The restoration, to some extent, of a protonmotive force to uncoupled cells by fatty acid addition is also supported by an increase in ATP synthesis as evidenced by a glucose synthesis with dihydroxyacetone as gluconeogenic substrate.

2,4-Dinitrophenol↗

PubMed1968

Respiratory Response of Acer pseudoplatanus Cells to Pyruvate and 2,4-Dinitrophenol.

The endogenous respiration rate of unstarved cultured cells of Acer pseudo-platanus L. is markedly stimulated by 2,4-dinitrophenol. Pyruvate is also stimulatory but to a lesser degree than dinitrophenol. Exogenously supplied sugars cause no short-term stimulation. Pyruvate does not enhance the elevated rate of O(2) uptake in the presence of dinitrophenol but does cause additional CO(2) evolution. The endogenous concentration of pyruvate is elevated in the presence of dinitrophenol. These observations suggest that the rate of O(2) uptake by the unstarved intact cells is limited by the rate of glycolysis and that rate of glycolysis is regulated by the intracellular concentration of adenine nucleotides or inorganic phosphate. Dinitrophenol stimulation of endogenous respiration is due in part to an indirect acceleration of glycolysis but also to a more direct facilitation of oxidation in the presence of excess mitochondrial substrate.

Journal Article↗

PubMed2001

The 143 and 300 K polymorphs of hexamethylenetetraminium 2,4-dinitrophenolate monohydrate.

The title compound, 3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane 2,4-dinitrophenolate monohydrate, C6H13N4+*C6H3N2O5-*H2O, the 1:1 hydrate adduct of hexamethylenetetramine (HMT) and 2,4-dinitrophenol, undergoes a temperature phase transition. In the room-temperature phase, the adduct crystallizes in the monoclinic P2(1)/m space group, whereas in the low-temperature phase, the adduct crystallizes in the triclinic P1 space group. This phase transition is reversible, with the transition temperature at 273 K, and the phase transition is governed by hydrogen bonds and weak interactions. In both these temperature-dependent polymorphs, the crystal structure is alternately layered with sheets of hexamethylenetetramine and sheets of dinitrophenol stacked along the c axis. The hexamethylenetetramine and dinitrophenol moieties are linked by intermolecular hydrogen bonds. The water molecule in the adduct plays an important role, forming O-H...O hydrogen bonds which, together with C-H...O hydrogen bonds, bridge the adducts into molecular ribbons. Extra hydrogen bonds and weak interactions exist for the low-temperature polymorph and these interconnect the molecular ribbons into a three-dimensional packing structure. Also in these two temperature-dependent polymorphs, dinitrophenol acts as a hydrogen-bond acceptor and HMT acts as a hydrogen-bond donor.

Journal Article↗

PubMed1983

The restorative action of coenzyme Q10 in 2,4-dinitrophenol-depressed electrical and contractile activities of guinea-pig heart.

With electrophysiological methods, mechanisms of the restorative action of coenzyme Q10 (CoQ10) in 2,4-dinitrophenol-depressed electrical and mechanical activities of isolated guinea-pig hearts were studied. Isoproterenol (3 X 10(-8) M)-induced action potential and contraction of the heart in 27 mM KCl Tyrode solution were abolished by 6 X 10(-6) M 2,4-dinitrophenol, while the additional application of CoQ10 (50 micrograms/ml) restored both these activities of the heart. This restorative action of CoQ10 was dose related (2 to 50 micrograms/ml) and was inhibited by 10 micrograms/ml 15-hydroperoxyarachidonic acid (15-HPAA) or pretreatment of the animals with indomethacin (5 mg/kg i.v.). When exogenously applied, 200 ng/ml prostacyclin also restored the 2,4-dinitrophenol-depressed electrical and contractile activities of the heart, but this restorative action of prostacyclin was affected neither by 15-HPAA nor by indomethacin pretreatment. These results suggest the possible participation of prostacyclin in the restorative action of CoQ10 in 2,4-dinitrophenol-depressed electrical and mechanical activities of the heart.

2,4-Dinitrophenol↗

PubMed1984

Hypothermic effect of 2,4-dinitrophenol infused ICV in the cat.

The effects of body temperature and behavior of 2,4-dinitrophenol injected into the cerebral ventricles of the cat was investigated in these experiments. Infused in a volume of 0.1-0.2 ml, 2,4-dinitrophenol produced a dose-dependent fall in body temperature, the duration of which was also dose-dependent. Apart from hypothermia, 2,4-dinitrophenol evoked mydriasis, respiratory irregularities, urination, vomiting, ataxia, muscular weakness, sedation and occasional clonic-tonic convulsions. Of all the autonomic effects, the most consistent was the effect on thermoregulation. The possible mechanisms of action in the brain of 2,4-dinitrophenol on the thermoregulatory mechanisms are discussed.

2,4-Dinitrophenol↗

PubMed1983

Analysis and kinetics of 2,4-dinitrophenol in tissues by capillary gas chromatography--mass spectrometry.

Five groups of six ICR mice were orally dosed with 22.5 mg/kg 2,4-dinitrophenol. Groups were sacrificed at 1, 3, 6, 12, and 24 h post treatment, and serum, liver, and kidney tissues were collected for analysis of dinitrophenol content. Quantitation was performed via a capillary gas chromatography--mass spectrometry technique after liquid--liquid extraction of biological specimens spiked with a trideuterated dinitrophenol internal standard. Concentration versus time data for each tissue were subjected to pharmacokinetic analysis. Similar two-compartment open models were found to characterize most phases of the disposition of this compound. The kidney appears to maintain a more persistent low concentration of 2,4-dinitrophenol.

2,4-Dinitrophenol↗

PubMed2002

Dinitrophenol pretreatment of rat ventricular myocytes protects against damage by metabolic inhibition and reperfusion.

We have investigated the protective effects of pretreatment with the mitochondrial uncoupler 2,4-dinitrophenol on the cellular damage induced by metabolic inhibition (with cyanide and iodoacetic acid) and reperfusion in freshly isolated adult rat ventricular myocytes. Damage was assessed from changes in cell length and morphology measured using video microscopy. Intracellular Ca(2+), mitochondrial membrane potential, and NADH were measured using fura-2, tetramethylrhodamine ethyl ester and autofluorescence, respectively. During metabolic inhibition myocytes developed rigor, and on reperfusion 73.6+/-8.1% hypercontracted and 10.8+/-6.7% recovered contractile function in response to electrical stimulation. Intracellular Ca(2+) increased substantially, indicated by a rise in the fura-2 ratio (340/380 nm) on reperfusion from 0.86+/-0.04 to 1.93+/-0.18. Myocytes pretreated with substrate-free Tyrode containing 50 microm dinitrophenol showed reduced reperfusion injury: 29.0+/-7.4% of cells hypercontracted and 65.3+/-7.3% recovered contractile function (P<0.001 vs control). The fura-2 ratio on reperfusion was also lower at 1.01+/-0.08. Fluorescence measurements showed that dinitrophenol caused mitochondrial depolarisation, and decreased NADH. The presence of the substrates glucose and pyruvate reduced these effects, and abolished the protection against damage by metabolic inhibition and reperfusion. However protection was unaffected by block of ATP-sensitive potassium channels. Thus the protective effects of pretreatment with dinitrophenol may result from a reduction in NADH in response to mitochondrial depolarisation.

Animals↗

PubMed1978

Uptake and metabolism of thyroid hormones by cultured monkey hepatocarcinoma cells. Effects of potassium cyanide and dinitrophenol.

Cultured monkey hepatocarcinoma cell (NCLP-6E) were used to investigate the uptake and metabolism of thyroid hormones. Intracellular accumulation was shown by the failure to acutely release hormone from cells subsequently exposed to serum proteins, and by the metabolic trnasformation of the hormones to deiodinated products and their sulfates. When hepatocarcinoma cell monolayers were studied at hormone concentrations below 10(-10) M, neither KCN nor dinitrophenol inhibited uptake. Taken together with previous findings that uptake was neither saturable nor reduced at low temperature, these results indicate that this process was not active transport. Deiodination of both the phenolic and non-phenolic rings, however, was partially inhibited by KCN but not by dinitrophenol. Sulfation of 3,3'-diiodothyronine and 3'-monoiodothyronine was strongly inhibited by both KCN and dinitrophenol. Uptake of the hormones and their metabolites was also measured in suspended hepatocarcinoma cells and compared with the uptake by normal rat hepatocytes, human fibroblasts and human lymphocytes. In these experiments 1 micrometer triidothyronine and 0.47 mM dinitrophenol were used to inhibit deiodination and sulfation, respectively. Uptake was similar in all cell types. Accumulation was highest with 3,5,3'-triiodothyronine, intermediate with other compounds having iodines in both rings, lowest with compounds iodinated in only one ring, and absent with iodothronine sulfates. These findings help to explain the relative rates of metabolism of the iodothyronines and their release from the cells.

Animals↗

PubMed2005

Aqueous atmospheric chemistry: formation of 2,4-dinitrophenol upon nitration of 2-nitrophenol and 4-nitrophenol in solution.

Field studies have shown that the powerful phytotoxic agent 2,4-dinitrophenol is very likely to form in the atmospheric aqueous phase upon nitration of 2-nitrophenol or 4-nitrophenol. However, until now, the nitration pathway and the relative importance of the two mononitrophenols as sources of 2,4-dinitrophenol were not known. The present study shows that 2,4-dinitrophenol formation from mononitrophenols can take place upon photolysis and photooxidation of nitrite/nitrous acid (NO2-/HONO) and that nitrogen dioxide plays a key role in the process. A possible pathway might be the reaction between light-excited mononitrophenols (both 2- and 4-isomers) and nitrogen dioxide, in the presence of oxygen. As an alternative, nitration might involve *NO3 + *NO2. Possible sources of nitrogen dioxide in the atmospheric aqueous phase are dissolution from the gas phase and oxidation of NO2-. In the latter case, however, it is necessary that NO2- oxidation is faster than the oxidation of mononitrophenols. This would happen, for instance, in the presence of hematite under irradiation. Radiation absorption and scattering by hematite would also inhibit the direct photolysis of nitrophenols. The formation rate and the yield of 2,4-dinitrophenol are slightly higher when starting from 2-nitrophenol than those from 4-nitrophenol, but they are compensated by the higher concentration of 4-nitrophenol in the atmospheric aqueous phase.

2,4-Dinitrophenol↗

PubMed2005

Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a "dietary supplement".

Dinitrophenol, a chemical currently used as an insecticide, is known to uncouple mitochondrial oxidative phosphorylation. A component of explosives, it has also been used in the past as a food coloring and clothing dye. In the 1930s, physicians prescribed it for weight loss, but this practice was discontinued when reports of cataracts, deaths, and other adverse outcomes came to light. We describe in our report the overdose and fatality of a teenager who purchased the product as a weight loss dietary supplement by mail order. We also describe a laboratory method that allowed postmortem determination of the dinitrophenol concentration in the victim's serum. Her death, despite prompt medical treatment, underscores the danger of dinitrophenol. The easy accessibility and apparent resurgent interest in dinitrophenol as a weight loss agent is extremely timely and troubling.

Adolescent↗

PubMed1998

Successful treatment of dinitrophenol poisoning in a child.

BACKGROUND: Poisoning with agricultural toxins is well known in the adult environment, but is rarely seen in children. Vancouver, British Columbia, borders on a large agricultural area, and the British Columbia Children's Hospital is the provincial referral center for major pediatric emergencies. In our experience, children from farming communities are vulnerable to a range of agriculturally related injuries, and exposure to toxic chemicals requiring hospitalization is not rare. METHODS: This is a case report with literature review. RESULTS: A child presenting in a coma proved later to have been exposed to a toxic agent. The agent, dinitrophenol, is a widely used agricultural herbicide and insecticide. The diagnosis resulted from a detailed history and physical examination, which revealed symptoms and signs that suggested poisoning. A search of the farm resulted, and the parents located open dinitrophenol containers. The toxic effects of dinitrophenol described in adults by Poison Control matched those present in the child, and specific treatment interventions existed that could be implemented to positively influence outcome. CONCLUSIONS: Awareness of the possibility of exposure to dinitrophenol is required, as death can result from exposure, and milder cases may go unrecognized. Appropriate treatment can improve outcome. Injuries with toxic agricultural agents are wholly preventable if the materials are handled appropriately in the farm environment, and parents whose children live on or visit farms are aware of the risks involved and take appropriate precautions.

Adult↗

PubMed2006

The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin.

Systemic deposition of transthyretin (TTR) amyloid fibrils is always observed in familial amyloidotic polyneuropathy, senile systemic amyloidosis and familial amyloidotic cardiomyopathy patients. Destabilization of the molecule leads to a cascade of events which result in fibril formation. The destabilization of a native protein with consequent conformational changes appears to be a common link in several human amyloid diseases. Intensive research has been directed towards finding small molecules that could work as therapeutic agents for the prevention/inhibition of amyloid diseases through stabilization of the native fold of the potentially amyloidogenic protein. This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures now determined allow a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.

2,4-Dinitrophenol↗

PubMed2001

Comparative study of toxicity of 4-nitrophenol and 2,4-dinitrophenol in newborn and young rats.

The toxicities of 4-nitrophenol and 2,4-dinitrophenol in newborn and young rats was examined and the susceptibility of newborn rats was analyzed in terms of presumed unequivocally toxic and no observed adverse effect levels (NOAELs). In the 18-day repeated dose newborn rat study, 4-nitrophenol was orally given from Day 4 to Day 21 after birth but did not induce any toxicity up to 160 mg/kg in the main study, although it induced death in one of six males at 160 mg/kg, and three of six males and one of six females at 230 mg/kg in a prior dose-finding study. In the 28-day repeated dose oral toxicity study starting at 6 weeks of age, 4-nitrophenol caused the death of most males and females at 1,000 mg/kg but was not toxic at 400 mg/kg except for male rat-specific renal toxicity. As unequivocally toxic levels were considered to be 230 mg/kg/day in newborn rats and 600 to 800 mg/kg/day in young rats, and NOAELs were 110 mg/kg/day in newborn rats and 400 mg/kg/day in young rats, the susceptibility of the newborn to 4-nitrophenol appears to be 2.5 to 4 times higher than that of young animals. In the newborn rat study of 2,4-dinitrophenol, animals died at 30 mg/kg in the dose-finding study and significant lowering of body and organ weights was observed at 20 mg/kg in the main study. In the 28-day young rat study, clear toxic signs followed by death occurred at 80 mg/kg but there was no definitive toxicity at 20 mg/kg. As unequivocally toxic levels and NOAELs were considered to be 30 and 10 mg/kg/day in newborn rats and 80 and 20 mg/kg/day in young rats, respectively, the toxicity of 2,4-dinitrophenol in newborns again seems to be 2 to 3 times stronger than in young rats. Abnormalities of external development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the toxic response in newborn rats is at most 4 times higher than that in young rats, at least in the cases of 4-nitrophenol and 2,4-dinitrophenol.

2,4-Dinitrophenol↗

PubMed1976

Inhibitory effects of scillaren and dinitrophenol on bilirubin excretion by the isolated perfused rat liver.

The effects of scillaren and dinitrophenol on bilirubin excretion by the perfused rat liver were studied. Both compounds inhibited bile flow, scillaren by 20 to 40%, and dinitrophenol by 60 to 80%. Bilirubin excretion was also impaired. However, the effect of scillaren on bilirubin excretion was less than that on bile flow, as indicated by an increase in the bile bilirubin concentration, whereas dinitrophenol had a greater effect on bilirubin excretion than on bile flow. Dinitrophenol also inhibited the hepatic removal of unconjugated bilirubin from the perfusate, probably because it impaired the initial uptake and/or storage of unconjugated bilirubin by the perfused liver.

Animals↗

PubMed1983

Role of membrane integral proteins in the modulation of red cell shape by albumin, dinitrophenol and the glass effect.

Defatted serum albumin is found to induce a cup shape in erythrocytes. At 40 mg/ml of albumin, approx. 80% of washed erythrocytes possess this morphology, which can be reversed to disc shape by dinitrophenol. Erythrocytes treated with trypsin, papain, pronase or neuraminidase show enhanced susceptibility to cup formation by albumin; however, chymotrypsinized erythrocytes exhibit a normal response. Red cells treated with concanavalin A (but not its succinylated derivative) show resistance to the cupping effect of albumin as well as the crenating effects of dinitrophenol and glass. The resistance develops after about 20 min following the exposure of cells to the lectin, and is rapidly abrogated on removal of the bound lectin by alpha-methylmannoside. Incubation of the concanavalin A-exposed cells at low temperature leads to prolongation of the time required to achieve the resistance. These results indicate an involvement of membrane integral proteins in mediating the shape modulating effects of albumin, dinitrophenol and exposure to glass.

2,4-Dinitrophenol↗

PubMed1985

Plasma levels and kinetic disposition of 2,4-dinitrophenol and its metabolites 2-amino-4-nitrophenol and 4-amino-2-nitrophenol in the mouse.

Eleven groups of six ICR mice were dosed orally with 22.5 mg/kg 2,4-dinitrophenol. Groups were sacrificed at 0, 0.5, 1, 2, 4, 6, 9, 12, 24, 48, and 96 h post-treatment and plasma was collected for analysis of dinitrophenol, 2-amino-4-nitrophenol, and 4-amino-2-nitrophenol content. Analyses were performed by capillary gas chromatography--mass spectrometry after liquid--liquid extraction of plasma specimens spiked with two internal standards. Quantification was based upon peak-area ratios of base peaks obtained from the three analytes and the trideuterated internal standards 2,4-dinitrophenol and 2-amino-4-nitrophenol. Plasma concentrations for each analyte versus their respective time periods were subjected to pharmacokinetic analysis. Of the two monoamine metabolites, 2-amino-4-nitrophenol was present in the greater amount and had an elimination half-life of 46 h from plasma while that of 4-amino-2-nitrophenol was 26 h.

2,4-Dinitrophenol↗