Superoxide alcohol formation

Sinaceur, J., Ribiere, C., Sabourault, D. and Nordmann, R. (1985). Superoxide formation in liver mitochondria during ethanol intoxication possible role in alcohol toxicity. In Free Radicals in Liver Injury (eds. G. Poli, K.H. Cheeseman, M.U. Dianzani and T.F. Slater) pp. 175-177. IRL Press, Oxford. 

The inactivation of enzymes containing the zinc-thiolate moieties by peroxynitrite may initiate an important pathophysiological process. In 1995, Crow et al. [129] showed that peroxynitrite disrupts the zinc-thiolate center of yeast alcohol dehydrogenase with the rate constant of 3.9 + 1.3 x 1051 mol-1 s-1, yielding the zinc release and enzyme inactivation. Later on, it has been shown [130] that only one zinc atom from the two present in the alcohol dehydrogenase monomer is released in the reaction with peroxynitrite. Recently, Zou et al. [131] reported the same reaction of peroxynitrite with endothelial NO synthase, which is accompanied by the zinc release from the zinc-thiolate cluster and probably the formation of disulfide bonds between enzyme monomers. The destruction of zinc-thiolate cluster resulted in a decrease in NO synthesis and an increase in superoxide production. It has been proposed that such a process might be the mechanism of vascular disease development, which is enhanced by diabetes mellitus. 

The stoichiometry of the oxidation appears to require the formation of potassium superoxide as one of the oxidation products, particularly at long reaction periods and high base concentrations. An oxidation of 3.00 mmoles of benzhydrol (0.12M) in the presence of 9.9 mmoles of potassium terf-butoxide (0.37M) in DMSO (80% )-ter -butyl alcohol (20%) absorbed 4.95 mmoles of oxygen in 27.7 minutes at 25°C. and yielded 2.2 mmoles of the benzophenone-DMSO adduct and 0.8 mmole of benzophenone. A precipitate formed (0.307 gram) which analyzed (23) as 103% (4.25 mmoles) potassium superoxide (K02). 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

Another problem with small models is that molecules from the solution (e.g. water) may come in and stabilise tetragonal structures and higher coordination numbers [224]. It is illustrative that very few inorganic con5)lexes reproduce the properties of the blue copper proteins [66,67], whereas typical blue-copper sites have been constructed in several proteins and peptides by metal substitution, e.g. insulin, alcohol dehydrogenase, and superoxide dismutase [66]. This shows that the problem is more related to protection from water and dimer formation than to strain. 

Pharmacology In vitro studies show that milk thistle reduces lipid peroxidation, scavenges free radicals, enhances superoxide dismutase, inhibits formation of leukotrienes, and increases hepatocyte RNA polymerase activity. In animal models, milk thistle protects against liver injury caused by alcohol, acetaminophen, and amanita mushrooms. The outcomes of clinical trials in patients with liver disease caused by alcohol have been mixed. In viral hepatitis and liver injury caused by amanita mushrooms, results of clinical trials have been mainly favorable. A commercial preparation of silybin (an isomer of silymarin) is available in some countries as an antidote to Amanita phalloides mushroom poisoning. 

At last, the HO2 radical is able to dissociate in and O2 Thus, in formate buffers exclusively Oj" is formed Alternatively, OH-radical scavengers like ethanol or other alcohols including t-butanol can be used instead of formate Usually, this method is less employed because of the lower yield of superoxide. 

NO reacts very rapidly with other free radicals like superoxide, ethyl alcohol radicals, or organic peroxyl radicals (Table 3). Physiological antioxidant defenses keep levels of such free radicals very low under normal conditions, but superoxide levels, in particular, can be dangerously increased after ischemia, acidosis, sepsis, or septic shock. The reaction leads to the formation of the noxious oxidant peroxynitrite ... 

Further evidence for an intermediate hydropero.xide was found in Zn -Fe -superoxide ex periments when PPh3 was added before tlie formation of the superoxide. This did not change the total amount of oxidation (ketone + alcohol), but did dramatically change the ketone to alcohol ratio in favor of alcohol. Hydroperoxides are. of course, rapidly reduced by PPli3 to alcohols. Furthermore when trimethyl phosphite is used instead of PPI13, the products of the reaction are phosphate and ketone. [7] Trimethyl phosphite is a reagent which reduces hydroperoxides at once to alcohols. This new trimethyl phosphite reaction can be understood better when we ask the question how is tlie hydroperoxide fonned ... 

If the crown catalyzed reaction of potassium superoxide with alkyl halide is carried out in dimethylsulfoxide as solvent, the product is the corresponding alcohol [6—9]. The formation of alcohol rather than dialkyl peroxide has been shown to result from reaction of the alkyl hydroperoxide anion with dimethylsulfoxide to form alkoxide and dimethylsulfone (Eqs. 8.3-8.5) [9]. The alkyl hydroperoxide anion is presumably formed by reduction of the initial alkyl hydroperoxide radical by the superoxide anion [8, 9]. 

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