Formaldehyde methanol metabolized

In rats and mice exposed to MTBE, unchanged MTBE and tert-butyl alcohol were shown to be the main respiratory excretion products. MTBE has also been found to be metabolized to formaldehyde, methanol, formic acid, carbon dioxide, 2-methyl-1,2-propanediol, and a-hydroxy-isobutyric acid. MTBE has not been shown to bioaccumulate in the tissues (ATSDR, 1996). 

ADH also has clinical significance in the metabolism of methanol and ethylene glycol, two drugs with toxic metabolites. Methanol is oxidized by ADH to formaldehyde, which damages the retina and can cause blindness. Ethylene glycol is metabohzed by ADH to oxalic acid, which has renal tox-... 

Methanol is metabolized to formaldehyde and formic acid, which injure the retinal cells and optic nerves, and lead to severe acidosis. Treatment delay increases morbidity. Thus, early recognition and management are crucial. Clinical features emerge up to 36 hours after ingestion. Nausea, vomiting, abdominal pain, headache, dizziness, paraesthesia, blurred vision, and diminished visual activity may occur, and coma supervenes. Dilated, unreactive, pupils predict permanent blindness. 

Animal species show great variability in mean lethal doses of methanol. The special susceptibility of humans to methanol toxicity is probably due to folate-dependent metabolism to formate and not to methanol itself or to formaldehyde, the intermediate metabolite. 

Methyl alcohol is poisonous and is commonly used to denature ethyl alcohol. Methanol poisoning results from ingestion, inhalation of methanol vapors, or absorption through the skin. Methanol is transformed in the body to formaldehyde (H2CO) by the enzyme alcohol dehydrogenase. The formaldehyde is then metabolized to formic acid (HCOOH)... 

The administration of ethanol to a patient suffering from methanol intoxication will competitively inhibit the metabolism of methanol to formaldehyde and... 

Ingesting methanol is indirectly harmful to one s eyes because in the body it is metabolized to formaldehyde—a chemical most toxic to living tissue. Methanol, just like ethanol, however, also has inherent toxicity and is thus also directly harmful. 

Ingestion of methanol, particularly during the prohibition era, resulted in significant illness and mortality. Where epidemics of methanol poisoning have been reported, one-third of the exposed population recovered with no ill effects, one-third have severe visual loss or blindness, and one-third have died. Methanol itself is not responsible for the toxic effects but is rapidly metabolized in humans by alcohol dehydrogenase to formaldehyde, which is subsequently metabolized by aldehyde dehydrogenase to form... 

The simplest alcohol, methanol, is commonly known as wood alcohol, because it was once obtained by heating wood in the absence of air, a process that also produced charcoal. Now methanol is synthesized from methane in natural gas. Methanol itself has a relatively low toxicity. However, methanol is oxidized (metabolized) in the liver to formaldehyde and then to formic acid, both of which are much more toxic. 

Methanol has been responsible for the deaths of many humans who ingested it accidentally or as a substitute for beverage ethanol. The fatal human dose is believed to lie between 50 and 250 g. In the body, methanol undergoes metabolic oxidation to formaldehyde and formic acid 1... 

Caution of Methyl Alcohol (Wood Alcohol) Methanol is commonly added to the rectified spirit, which makes it unfit to drink. Mixing methanol with alcoholic beverages results in methanol poisoning. Methanol is metabolized to formaldehyde and formic acid by aldehyde dehydrogenase. High blood levels (750 mg/dL) cause severe poisoning, which leads to blindness and even death. 

An example of biotoxification is the formation of paraoxon from the insecticide parathion via sulfoxidation. The simple substitution of an oxygen atom for a sulfur atom in the molecule results in a cholinesterase inhibitor with several times more potency. Similarly, the toxic action of methanol in producing blindness is the result of its metabolism to formaldehyde. Examples of bioactivation and biotoxification reactions are shown in Figure 3.2. 

Tetrahydrofolate functions as a carrier of one-carbon units. There are numerous metabolic reactions that require either the addition or removal of a one-carbon unit of some specific oxidation state. THF binds one-carbon units of three oxidation levels the methanol, formaldehyde, and formate states. These are shown in Table 6.4 along with their origins and uses. The various one-carbon units are interconvertible, as shown in Figure 6.5. Nicotinamide coenzymes are involved. In addition, the one-carbon unit may be released as C02. The methanol-level THF-bound one-carbon unit 5-methyl-THF is the storage and transport form. Once formed, its main pathway of metabolism is to form methionine from homocysteine, a reaction that requires vitamin B12 in the form of methylcobalamin (see Figure 6.2 and Chapter 20) ... 

E5-2 When 13C-labelled formaldehyde, 13CH20, is fed to live cultures of bacteria in an NMR spectrometer, the metabolism of the label can be followed by 13C NMR. Many bacterial species produce roughly equal amounts of formate (HCOO ) and methanol (CH3OH). This is reminiscent of the purely chemical Cannizzaro reaction in which a hydride ion (H ) is transferred directly from one formaldehyde molecule to another. The accompanying 61 MHz deuterium NMR spectra are of methanol that results from the metabolism of deuterium-labelled formaldehyde, CD2O, by Escherichia coli and Pseudomonas putida. What do they tell us about possible Cannizzarase enzymes in those organisms ... 

It is clear from the spectrum that P. putida metabolizes formaldehyde by some sort of Cannizzarase, as the bulk of the methanol produced is CD3OH. The actual mechanism turns out to be quite unlike that of the chemical Cannizzaro reaction - see the reference below for details. 

Disposition in the Body. Formic acid is an intermediate in normal metabolism when administered it probably takes part in the metabolism of I -carbon compounds to produce methyl groups it is excreted in the urine and also undergoes oxidation to carbon dioxide. Together with formaldehyde, it is a metabolite of methanol and the two are probably mainly responsible for the effect of methanol on vision. 

Beyond metabolism of carbohydrates, there are several other biological processes common in prokaryotes that consume oxygen. For example, methylotrophic organisms can metabolize Ci compounds such as methane, methanol, formaldehyde, and formate, as in... 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Intoxication may present as inebriation and drowsiness similar to ethanol use. Other symptoms are vomiting, diarrhea, delirium and agitation, back and abdominal pain, and clammy skin. Toxic effects usually follow a latent period of several hours. Formate inhibits mitochondrial cytochromes resulting in neurotoxicity. Ocular signs include blurred vision, dilated pupils, and direct retinal toxicity with optic disc hyperemia and ultimately permanent blindness [91]. Cerebral hemorrhagic necrosis has been reported [92]. Severe poisoning may result in Kussmaul respiration, inspiratory apnea, coma, and death. Urine samples may have the characteristic smell of formaldehyde. An elevated serum osmolal gap from methanol will be evident early in presentation but may disappear after approximately 12 hours. At this time, an elevated anion gap metabolic acidosis from retained formate may be evident. 

In industry, exposure to formic acid can occur through the oral, dermal, and inhalation routes. Formic acid can also be produced in the mouth and stomach from ingested formaldehyde. Formic acid can also be produced in the liver and other organs from the metabolism of methanol and formaldehyde. Stings by bees, wasps, and ants may result in the subcutaneous injection of formic acid. 

Formic acid can be readily absorbed from the digestive tract and the respiratory system. Systemic absorption produces acidosis, neuropathy, and visual and mental disturbances. Acidosis can also be produced when formic acid is produced by liver aldehyde dehydrogenase from formaldehyde. Formaldehyde in turn can also be produced metabolically by alcohol dehydrogenase from methanol. Formic acid is oxidized to carbon dioxide by the folate-dependent pathway. Some formic acid is excreted unchanged in the urine. 

Another feature that may influence the epididymal toxicity of an agent is the presence of metabolizing enzymes within the epididymis. The basal cells of the epididymis contain alcohol dehydrogenases capable of oxidizing small alcohols (i.e., methanol and ethanol) to aldehydes (i.e., formaldehyde and... 

Aspartame is completely metabolized in the gut and absorbed as aspartic acid, phenylalanine, methanol, and diketopiperazine. Above 86°F, the methanol in aspartame decays forming formaldehyde and formic acid. When ingested, methanol attacks the eyes, CNS, and the GI tract and can damage the liver and kidneys. I26l Formaldehyde and formic acid are corrosive to mucous membranes and can result in liver and kidney injury and disease when ingested. I26l Formic acid is an established human toxin. Phenylalanine is believed to mediate or exacerbate hepatic encephalopathy. I44,45 ... 

A 55-year-old woman and a 34-year-old man ingested, with suicidal intent, an unknown amount of what was reported to have been formalin (Koppel et al. 1990). The female patient was found in a coma and admitted to the hospital with shock (systolic blood pressure 50 mm Hg), respiratory insufficiency, and metabolic acidosis. The male patient, who had a history of alcohol abuse, was also hospitalized with shock (systolic blood pressure 60 mm Hg), respiratory insufficiency, and metabolic acidosis. Both patients underwent hemodialysis and hemofiltration treatment. Analysis of the formaldehyde samples ingested by both patients showed no evidence that these products contained methanol, although it was expected to have been detected. A chemical-toxicological screening indicated that no drugs other than fonnaldehyde had been ingested neither methanol or ethanol were detected in blood samples. Three... 

Matsumoto K, Moriya F, Nanikawa R. 1990. The movement of blood formaldehyde in methanol intoxication. II Tire movement of blood formaldehyde and its metabolism in the rabbit. Jpn J Legal Med 44(3) 205-211. 

Competitive inhibition is the basis for the treatment of some intoxications (e.g., methyl alcohol, ethylene glycol). Methanol, which is widely used industrially as a solvent, is added to ethanol (ethyl alcohol) to make it unsuitable for human consumption. Such adulterated alcohol is commonly known as denatured alcohol. Methanol is metabolized primarily in the liver and kidney by oxidation to formaldehyde and formic acid ... 

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