Metabolites of methanol

Methanol intoxication can cause blindness due to damage to ganglion cells in the retina. The blindness results from the accumulation of formaldehyde and formic acid, which are metabolites of methanol. Chemical compounds can also damage the visual cortex, for example, visual damage was observed among the victims of organic mercury intoxication in Japan (the fishermen of Minamata Bay). ... 

The most characteristic symptom in methanol poisoning is a visual disturbance, frequently described as "like being in a snowstorm." A complaint of blurred vision with a relatively clear sensorium should strongly suggest the diagnosis of methanol poisoning. Since much of the toxicity is due to metabolites of methanol, there is often a delay of up to 30 hours before development of visual disturbances and other signs of severe intoxication. 

A metabolite with +16 amu is generally suspected of forming by hydrox-ylation (or by some other reaction involving the addition of oxygen). However, a metabolite with +14 amu is often suspected of forming by methylation (+CH2), not by a combination of the addition of oxygen (+16) and dehydrogenation (—2). NADPH-fortified human liver microsomes cannot catalyze the methylation of dmg candidates (such reactions are catalyzed by cytosolic enzymes in the presence of. S -adenosylmethionine). However, methylation can sometimes occur as an artifact when mass spectrometry is conducted in the presence of methanol (164), and [M + 12] adducts can form from condensation reactions with formaldehyde, which is a microsomal metabolite of methanol (165). A metabolite with +30 amu is indicative of either formation of a carboxylic acid metabolite or a combination of hydroxylation (+16) and methylation (+14). Only the former can be catalyzed by NAPDH-fortified liver microsomes. 

Disposition in the Body. Rapidly metabolised in the body tissues to formic acid and methanol, especially in the liver and erythrocytes the formic acid may then be excreted in the urine as formates, or metabolised to labile methyl groups. Formaldehyde is a metabolite of methanol. 

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. 

Headspace gas chromatographic analysis is the method of choice for the measurement of methanol. An adaptation of this technique may be used to measure formate, the toxic metabolite of methanol, after esterification to methyl formate. These methods are included in the Chapter 34 Appendix that is found on the book s accompanying Evolve site (http //evolve.elsevier.com/Tiet2/textbook/). An enxy-matic assay based on formate dehydrogenase has also been reported. 

Formic acid is readily metabolized and eliminated by the body. Nonetheless, it has specific toxic effects the formic acid and formaldehyde produced as metabolites of methanol are responsible for the optic nerve damage, causing blindness seen in methanol poisoning. Some chronic effects of formic acid exposure have been documented. Some animal experiments have demonstrated it to be a mutagen, and chronic exposure may cause liver or kidney damage. Another effect of chronic exposure is development of a skin allergy that manifests upon re-exposure to the chemical. 

Compounds Causing Cardiovascular Toxicity Alcohols are the most important compounds causing vascular toxicity. Ethanol depresses cardiac muscle and attenuates its contractivity when the concentration of ethanol in the blood exceeds 0.75 mg/100 mL. Ethanol also causes arrhythmias, and a metabolite of ethanol, acetaldehyde, also depresses the heart. Furthermore, high concentrations of acetaldehyde cause cardiac arrhythmias. The cardiovascular toxicity of methanol is about the same as that of ethanol, whereas al cohols with longer chains are more toxic than ethanol. 

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-... 

In subsequent smdies, it was shown that, atfer hydrolysis, about 42% of the total radioactive residue in grain may be identified as 4-fert-butylcyclohexanone. Moreover, 34-90% of the TRR was extracted by heating the plant material under reflux with a mixture of methanol and hydrochloric acid. The performance of that method was properly demonstrated by individual fortification experiments with the parent compound and the three primary metabolites (bold in Figure 1). 

Ethylenethiourea (ETU) is a toxic decomposition product/metabolite of alky-lenebis(dithiocarbamates). This compound could be generated during processing of treated crops at elevated temperature. Different chromatographic methods to determine the residue levels of ETU have been published. After extraction with methanol, clean-up on a Gas-Chrom S/alumina column and derivatization (alkylation) with bro-mobutane, ETU residues can be determined by GC with a flame photometric detector in the sulfur mode. Alternatively, ETU residues can also be determined by an HPLC method with UV detection at 240 nm or by liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/tandem mass spectrometry (LC/MS/MS) (molecular ion m/z 103). ... 

Organic solvent extraction. Two analytical methods for acetamiprid have been developed One method is for the parent only and the other determines the total residue of the parent and its metabolites (lM-1-2, lM-1-4 and lC-0). Air-dried soil (20-g equivalent dry soil) is weighed into a centrifuge tube and imidacloprid residue is extracted with 100 mL of methanol-0.1M ammonium chloride (4 1, v/v) using a mechanical shaker for about 30 min. After shaking, the tube is centrifuged at 8000 rpm for 2 min. The supernatant is filtered and the analysis of the soil residue is carried out in the same manner as described above for the parent compound. 

Plant samples are homogenized with sodium hydrogencarbonate aqueous solution to prevent decomposition of the analytes during homogenization. Imibenconazole and its primary metabolite, imibenconazole-debenzyl, are extracted from plan materials and soil with methanol. After evaporation of methanol from the extracts, the residues are extracted with dichloromethane from the residual aqueous solution. The dichloromethane phase is cleaned up on Florisil and Cig columns. Imibenconazole and imibenconazole-debenzyl are determined by gas chromatography/nitrogen-phosphorus detection (GC/NPD). 

Mills and Thurmen [105] used a mixed method for the isolation of triazine herbicide metabolites from aquifer sediments using automated solid phases extraction with a mixture of methanol and water (4 1 V/V). Following evaporation of the methanol phases, the metabolites were collected in a column of Cl8 octadecyl resin. The analytes were then stripped from the column with ethyl acetate leaving impurities on the column. Down to O.lpg kg-1 triazine could be determined. 

Determination of various analgesic and antipyretic pharmaceuticals on reversed phase has included not only the analysis of serum levels of aspirin, salicylic acid and salicyluric acid using acidified acetonitrile (557), or methanol (338), but also suUinpyrazone under isocratic conditions (339), and 6-chloro-a-methylcarbazole-2-acetic acid (340). The polar thiol metabolites of acetaminophen were analyzed by RPC and the method was found to be superior to other chromatographic techniques used in this analysis (341). 

The new metabolite from Red Sea marine invertebrates, Asmarine B (169), presents a hydroxylamine functional group (equation 50). When treated with acetic anhydride at room temperature the Asmarine B (169) underwent an unexpected [3,3]-sigmatropic rearrangement to give 170. After 1,6-addition of methanol and concomitant loss of acetic acid 170 produced the pyrimidine 171. ... 

In Vitro Salicylic Acid Metabollsmi Protein fractions were assayed for their ability to produce the same metabolite of salicylic acid as the root tissue produced. Protein fractions (50-185 pL) were incub ed In an assay mixture containing 0.4 mM salicylic acid, 25 pCl [ C]-sallcyllc acid, 1 mM UDPG, 25 mM Tris-Mes buffer to adjust to pH 7.0 (total volume 200 pi), for 1 h at 30 °C. The reaction was stopped by adding 200 pL absolute methanol. 

Management of methanol and ethylene glycol poisoning is similar. Symptomatic support of respiration and circulation is augmented by correction of metabolic acidosis with intravenous bicarbonate infusion, and control of seizures with diazepam. Ethanol inhibits the metabolism of methanol and ethylene glycol to the toxic metabolites, and can give time for further treatment. The goal is to maintain blood ethanol concentrations between 100 and 150 mg per decilitre, sufficient to saturate alcohol... 

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. 

Fomepizole Inhibits alcohol dehydrogenase, prevents conversion of methanol and ethylene glycol to toxic metabolites Methanol and ethylene glycol poisoning Orphan drug. Toxicity Headache, nausea, dizziness, rare allergic reactions... 

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