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PubMed1985

Elevated endogenous breath acetaldehyde levels among abusers of alcohol and cigarettes.

Endogenous (fasting) breath acetaldehyde levels were assessed as a discriminator between alcoholic and non-alcoholic subjects. The influence of smoking as a potential confounding variable on breath acetaldehyde was determined. Individuals with a history of smoking and/or drinking had higher endogenous breath acetaldehyde levels as compared to controls. Mean acetaldehyde levels revealed an additive (noninteractive) pattern associated with combined abuse of these substances. The similarity in acetaldehyde levels between alcoholic non-smokers and non-alcoholic smokers limits the usefulness of endogenous breath acetaldehyde for the purpose of early diagnosis of alcoholism. Results support hypotheses that elevations in acetaldehyde could be a common factor in disease associated with alcohol and cigarette abuse.

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PubMed1989

Comparative subchronic oral toxicity of sulphite and acetaldehyde hydroxysulphonate in rats.

A subchronic oral toxicity study of sodium metabisulphite and acetaldehyde hydroxysulphonate was conducted in normal and sulphite oxidase-deficient rats. At the highest dose level (350 mg SO2 equiv./kg body weight/day for 3 wk followed by 175 mg SO2 equiv./kg body weight/day for 5 wk of either compound), gastric lesions were noted histologically in both normal and sulphite oxidase-deficient rats. The lesions were more severe and more frequently encountered in the sulphite oxidase-deficient rats. The no-effect level for Na2S2O5 was 70 mg SO2 equiv./kg body weight/day in both normal and sulphite oxidase-deficient rats. Liver lesions were noted in rats treated with acetaldehyde hydroxysulphonate. These lesions may possibly be attributable to the effects of free acetaldehyde. The no-effect level for acetaldehyde hydroxysulphonate was 7 mg SO2 equiv./kg body weight/day for sulphite oxidase-deficient rats and 70 mg SO2 equiv./kg body weight/day for normal rats. Increased urinary excretion of sulphite was noted in sulphite oxidase-deficient rats whether or not they were given exogenous sulphites. An increase in urinary sulphite levels in sulphite oxidase-deficient rats was observed after dosing with acetaldehyde hydroxy-sulphonate. These findings suggest that acetaldehyde hydroxysulphonate is metabolized to acetaldehyde and free sulphite.

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PubMed1994

Investigations on the ethanol-induced flushing reaction: effects of propranolol and dipyridamole on acetaldehyde and prostacyclin metabolism.

Disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, induces a flushing reaction upon the ingestion of ethanol, exerting aversion against alcohol that has been used in the treatment of alcoholism. This unpleasant response has been associated with an accumulation of acetaldehyde, and more recently, with an increase in vascular prostacyclin (PGI2) production. To evaluate the possibility of evoking the flushing reaction with drugs less toxic than disulfiram, we studied the effects of propranolol and dipyridamole on ALDH and PGI2. Acetaldehyde oxidation rate was assessed by gas chromatography in mitochondria from rats treated with these drugs for seven days. Prostacyclin generation was determined in rat aortic rings incubated in Krebs-Ringer with these drugs separately and associated to acetaldehyde, and measured by radioimmunoassay of 6-keto-PGF1 alpha. Propranolol inhibited acetaldehyde oxidation rate whereas dipyridamole did not. Furthermore, propranolol increased blood acetaldehyde levels without affecting ethanol elimination rate. Both drugs stimulated prostacyclin synthesis but only dipyridamole enhanced the stimulatory effect of acetaldehyde on vascular prostacyclin production. These results strongly suggest the possibility of producing a deterrent effect on the consumption of alcohol by using propranolol or dipyridamole. In contrast to disulfiram, these drugs could potentially induce the flushing reaction in humans in the presence of low acetaldehyde concentrations; this new therapeutic approach might have an important clinical and toxicological relevance.

Acetaldehyde↗

PubMed1985

Inhibition of mitochondrial aldehyde dehydrogenase and acetaldehyde oxidation by the glutathione-depleting agents diethylmaleate and phorone.

Experiments were carried out to study the effect of two commonly used glutathione-depleting agents, diethylmaleate and phorone, on the oxidation of acetaldehyde and the activity of aldehyde dehydrogenase. The oxidation of acetaldehyde by intact hepatocytes was inhibited when the cells were incubated with diethylmaleate. Washing and resuspending the cells in diethylmaleate-free medium afforded protection against the inhibition of acetaldehyde oxidation. The oxidation of acetaldehyde by isolated rat liver mitochondria as well as by disrupted mitochondria in the presence of excess NAD+ was inhibited by diethylmaleate or phorone, indicating inhibition of the low-Km aldehyde dehydrogenase. In addition, diethylmaleate inhibited oxidation of acetaldehyde by the high-Km cytosolic aldehyde dehydrogenase. Significant accumulation of acetaldehyde occurred when ethanol was oxidized by hepatocytes in the presence, but not in the absence, of diethylmaleate. Thus, diethylmaleate blocks the oxidation of added or metabolically generated acetaldehyde, analogous to results with other inhibitors of the low-Km aldehyde dehydrogenase such as cyanamide. These results suggest that caution should be used in interpreting the effects of diethylmaleate or phorone on metabolic reactions, especially those involving metabolism of aldehydes such as formaldehyde, because, in addition to depleting glutathione, these agents inhibit the low-Km aldehyde dehydrogenase.

Acetaldehyde↗

PubMedDate not supplied

Use of cyanamide to determine localization of acetaldehyde metabolism in rat liver.

Various techniques have been employed previously to show that acetaldehyde is primarily oxidized in the mitochondrial matrix of rat liver. In this study, a new approach was tested. Mitochondrial low-Km aldehyde dehydrogenase (ALDH) was partially inactivated and the effect on acetaldehyde oxidation measured. Cyanamide was chosen as the ALDH inhibitor. An enzymatic activation of cyanamide, probably by catalase, was necessary for the drug to inhibit ALDH activity. The level of remaining ALDH activity after cyanamide treatment was correlated with the ability of either rat liver mitochondria or liver slices to oxidize acetaldehyde. Any inhibition of ALDH resulted in a decreased rate of acetaldehyde oxidation, indicating that there is no excess of ALDH in the cell above what is needed to oxidize acetaldehyde. Approximately 15% of the acetaldehyde disappearance at 200 microM was catalyzed by high-Km ALDH, and nearly 30% of the acetaldehyde was lost through binding to cytosolic proteins.

Acetaldehyde↗

PubMedDate not supplied

Effects of acetaldehyde on membrane potentials of sinus node pacemaker fibers.

The experiments reported here were performed to characterize the effects of acetaldehyde on membrane potentials (MP) of sinus node subsidiary pacemaker fibers in the absence and presence of adrenergic and cholinergic blockade. Guinea pig sinoatrial preparations were superfused with Tyrode's solution at 37 degrees C while electrically stimulated at 5 Hz. Intracellular microelectrodes were used to record the MP of sinus node subsidiary pacemaker fibers. Acetaldehyde 3 x 10(-6) M and 3 x 10(-3) M had no effect on maximum diastolic potential (MDP), while 3 x 10(-5) M and 3 x 10(-2) M exerted a depolarizing effect on the MDP, without affecting the overshoot (OS). The fall in MDP was associated with a reduction in the amplitude of the action potential (AAP) and the maximum velocity of phase 0 (Vmax 0). The depressant effect of acetaldehyde on MDP was not abolished by adrenergic blockers or atropine. Concentrations of acetaldehyde between 3 x 10(-5) and 3 x 10(-2) M prolonged the action potential duration (APD). Acetaldehyde 3 x 10(-3) M did not affect MDP even in the presence of atropine or propranolol. The APD-prolonging effect of acetaldehyde was not abolished by adrenergic blockers. In summary, the actions of acetaldehyde on MDP and APD were independent of adrenergic and cholinergic mechanisms.

Acetaldehyde↗

PubMedDate not supplied

The effect of cigarette smoking on breath and whole blood-associated acetaldehyde.

Six pairs (1 habitual smoker and 1 nonsmoking control) of volunteers were studied to determine the effect of smoking tobacco on breath and whole blood acetaldehyde levels. On a given study day, samples of blood and breath were obtained from both participants at -0.25, 0, 0.25, 0.50, 0.75, 1.5, 2.5, and 3.5 hour time points. The smoking volunteer was told to smoke 1-3 cigarettes between the 0 and 0.25 hour time points. Acetaldehyde levels in breath and whole blood were quantified with a fluorigenic high performance liquid chromatographic assay. Acetaldehyde in breath rose six-fold in smokers at the 0.25 hour time point and returned to levels not significantly different from baseline values found in smokers or nonsmokers by 0.50 hr. Whole blood-associated acetaldehyde measurements remained unchanged in smokers throughout the experiment and were not different from nonsmokers. In conclusion, while smoking produces appreciable levels of acetaldehyde in expired air, the partitioning of acetaldehyde associated with smoking to blood or blood proteins appears to be below the level of detection of the assay employed (picomolar). Smoking of tobacco products may not interfere with assays designed to quantify ethanol intake by measuring acetaldehyde adducts with blood proteins.

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PubMed1995

Acetaldehyde: genotoxicity and cytotoxicity in human lymphocytes.

We evaluated the DNA damaging effects of ethanol and its major metabolite, acetaldehyde. Freshly isolated human lymphocytes from two healthy donors were incubated with 0, 1.56, 6.25, 25, and 100 mM of ethanol or acetaldehyde in complete medium for 1 h. We used a newly developed, sensitive, alkaline microgel electrophoresis technique to quantitate single- and double-strand DNA breaks or alkali-labile sites in individual cells. Ethanol did not induce DNA strand breaks. However, acetaldehyde induced both single-strand (even at the lowest concentration of 1.56 mM) and double-strand breaks (only at the highest concentration of 100 mM). Following exposure to acetaldehyde, cells were incubated in complete medium for 30, 60, and 120 min. During this incubation period, most cells were unable to repair DNA single- and double-strand breaks caused by acetaldehyde. We also observed a significant cell loss after exposure to acetaldehyde. To our knowledge, this is the first study demonstrating DNA single- and double-strand breaks by acetaldehyde.

Acetaldehyde↗

PubMedDate not supplied

Use of an "acetaldehyde clamp" in the determination of low-KM aldehyde dehydrogenase activity in H4-II-E-C3 rat hepatoma cells.

The high-affinity (K(M)<1 microM) mitochondrial class 2 aldehyde dehydrogenase (ALDH2) metabolizes most of the acetaldehyde generated in the hepatic oxidation of ethanol. H4-II-E-C3 rat hepatoma cells have been found to express ALDH2. We report a method to assess ALDH2 activity in intact hepatoma cells that does not require mitochondrial isolation. To determine only the high-affinity ALDH2 activity it is necessary to keep constant low concentrations of acetaldehyde in the cells to minimize its metabolism by high-K(M) aldehyde dehydrogenases. To maintain both low and constant concentrations of acetaldehyde we used an "acetaldehyde clamp," which keeps acetaldehyde at a concentration of 4.2+/-0.4 microM. The clamp is attained by addition of excess yeast alcohol dehydrogenase, 14C-ethanol, and oxidized form of nicotinamide adenine dinucleotide (NAD(+)) to the hepatoma cell culture medium. The concentration of 14C-acetaldehyde attained follows the equilibrium constant of the alcohol dehydrogenase reaction. Thus, 14C-acetate is generated virtually by the low-K(M) aldehyde dehydrogenase activity. 14C-acetate is separated from the culture medium by an anionic resin and its radioactivity is determined. We showed that (1) acetate production is linear for 120 min, (2) addition of 160 microM cyanamide to the culture medium leads to a 75%-80% reduction of acetate generated, and (3) ALDH2 activity is dependent on cell-to-cell contact and increases after cells reach confluence. The clamp system allows the determination of ALDH2 activity in less than one million H4-II-E-C3 rat hepatoma cells. The specificity and sensitivity of the "acetaldehyde clamp" assay should be of value in evaluation of the effects of new agents that modify Aldh2 gene expression, as well as in the study of ALDH2 regulation in intact cells.

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PubMed2006

The effect of acetaldehyde-glycosaminoglycan mixtures upon Factor IXa and Factor IX-Deficient Plasma.

Earlier studies have shown that acetaldehyde, the primary intermediate in the biological degradation of ethanol, interacts with enzymes and zymogens of the common coagulation pathway, prolonging prothrombin time and activated partial thromboplastin time (APTT), and that acetaldehyde-glycosaminoglycans (GAGs) mixtures synergistically prolong clotting times (Brecher, A. S. (2005). In Comprehensive Handbook of Alcohol Related Pathology. Vol. 3(93), pp. 1223-1244). In this study, the effect of acetaldehyde and GAGs upon Factor IXa, an intrinsic pathway enzyme, has been investigated. Individually, acetaldehyde, heparins of various molecular weights, dermatan sulfate, and chondroitin sulfates A and C affect Factor IXa, prolonging clotting time as measured by APTT. Pre-incubation of Factor IXa with a mixture of 22.3 mM acetaldehyde and heparin(17k), heparin(6k), dermatan sulfate, or chondroitin sulfate A additively prolongs clotting times, reflecting individual, unrelated molecular mechanistic effects. In contrast, a synergistic effect is observed at the 44.7 mM acetaldehyde level with heparin(17k), heparin(3k), chondroitin sulfates A and C, and dermatan sulfate, suggesting that acetaldehyde may cross-link with the enzyme and the GAGs, forming tertiary complexes, further influencing coagulopathy. These observations upon Factor IXa present a deeper dimension to the anticoagulation effect of alcohol on the coagulation cascade.

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PubMed2004

Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid.

In hepatocytes ethanol (EtOH) is metabolized to acetaldehyde and to acetate. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) are said to protect the liver against alcohol. We investigated the influence of ethanol and acetaldehyde on alcohol dehydrogenase (ADH)-containing human hepatoma cells (SK-Hep-1) and the protective effects of UDCA and TUDCA (0.01 and 0.1 mM). Cells were incubated with 100 and 200 mM ethanol, concentrations in a heavy drinker, or acetaldehyde. Treatment with acetaldehyde or ethanol resulted in a decrease of metabolic activity and viability of hepatocytes and an increase of cell membrane permeability. During simultaneous incubation with bile acids, the metabolic activity was better preserved by UDCA than by TUDCA. Due to its more polar character, acetaldehyde mostly damaged the superficial, more polar domain of the membrane. TUDCA reduced this effect, UDCA was less effective. Damage caused by ethanol was smaller and predominantly at the more apolar site of the cell membrane. In contrast, preincubation with TUDCA or UDCA strongly decreased metabolic activity and cell viability and led to an appreciable increase of membrane permeability. TUDCA and UDCA only in rather high concentrations reduce ethanol and acetaldehyde-induced toxicity in a different way, when incubated simultaneously with hepatocytes. In contrast, preincubation with bile acids intensified cell damage. Therefore, the protective effect of UDCA or TUDCA in alcohol- or acetaldehyde-treated SK-Hep-1 cells remains dubious.

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PubMed2005

Maximum exposure levels for xylene, formaldehyde and acetaldehyde in cars.

Although millions of individuals are exposed to emissions from articles inside cars, relatively little has been published about possible adverse health effects and about exposure levels that can be considered safe or "acceptable". Xylene, formaldehyde and acetaldehyde represent typical examples of relevant volatile organic substances (VOC) released from articles inside cars. Recently, a concept for derivation of maximum exposure levels for volatile organic substances in cars has been published. In the present study we applied this concept to derive maximum exposure levels for xylene, formaldehyde and acetaldehyde and compared the resulting concentrations to exposure levels usually found inside of cars. We derived Short Term Exposure Levels Inside Automotive Vehicles (STELIA) of 29, 0.125 and 15.3 mg/m(3) for xylene, formaldehyde and acetaldehyde, respectively. These STELIAs should not be exceeded during short-term exposures, for instance when starting a car that had been heated up during parking in the sun. Exposure Levels Inside Automotive Vehicles (ELIA, chronic) for chronic exposure to non-genotoxic substances were 8.8, 0.125 and 0.635 mg/m(3) for systemic as well as 17.6, 0.125 and 1.7 mg/m(3) for local exposure to xylene, formaldehyde and acetaldehyde, respectively. Although, it is known that exposure limits for carcinogenic substances should be treated with caution, encouraged by the well documented threshold mechanisms we nevertheless derived ELIAs for Carcinogenic and Mutagenic Substances (ELIA, cm) resulting in 0.125 and 0.635 mg/m(3) for formaldehyde and acetaldehyde. If these ELIAs are matched against average concentrations of xylene, formaldehyde and acetaldehyde found in cars at 23 degrees C (1.22, 0.048 and 0.042 mg/m(3)), there is no reason for concern. With respect to STELIAs and extrapolated concentrations at 65 degrees C (14.7, 1.47 and 1.68 mg/m(3), for xylene, formaldehyde and acetaldehyde, respectively), however, a reduction of the concentration of formaldehyde may be necessary.

Acetaldehyde↗

PubMed1980

Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination.

Alcoholics and controls given ethanol (1.2 g/kg body weight) were analyzed for blood and breath acetaldehyde using the more sensitive and reliable semicarbazide method. The acetaldehyde levels in controls were almost undetectable (less than 2 microM), but were found to be elevated (10--10 microM) in 6 of 8 alcoholics. Breath acetaldehyde and blood acetaldehyde co-fluctuated during the experiments. Fructose infusion transiently increased blood acetaldehyde, but only in 4 of the alcoholics. The apparent discrepancy between our finding and the simultaneously reported low acetaldehyde level in alcoholics (Eriksson and Peachy, this volume) may be explained by the different status of the alcoholics tested. Our alcoholics were tested on the day after hospital admission and eliminated ethanol 5% faster than controls. It is suggested that elevated blood acetaldehyde occurs regularly after interrupted drinking in heavy alcohol abusers with fast ethanol elimination, possibly combined with reduced liver aldehyde dehydrogenase activity, but that the phenomenon may rapidly disappear upon abstinence and hospital treatment, which reduces disturbances in hepatic functions and the ethanol elimination rate.

Acetaldehyde↗

PubMed1997

Voluntary alcohol drinking and acetaldehyde metabolism in F2 hybrid crosses of AA and ANA rat lines.

Alcohol-preferring AA and alcohol-avoiding ANA rat lines differ in their acetaldehyde metabolism and this has been suggested to be one reason for their different ethanol drinking behavior. To study whether acetaldehyde accumulation is indeed associated with alcohol drinking behavior and to evaluate which enzymatic differences previously observed in these rat lines are of importance in this regard, we produced an F2 generation from them. ADH and ALDH activities, and ALDH patterns were then assessed from these hybrids and correlated with their voluntary ethanol drinking and blood acetaldehyde concentrations measured during ethanol metabolism. A significant negative correlation between voluntary ethanol intake and blood acetaldehyde concentration was observed in F2 females drinking less than 17% of the total fluid as ethanol. In F2 males, hepatic microsomal high Km ALDH activities correlated negatively with blood acetaldehyde concentrations, indicating that low activity of this isoenzyme in ANA rats could be at least in part responsible for the accumulation of acetaldehyde in their blood. Finally, F2 rats that possessed the cytosolic ALDH isoenzyme pattern most frequently found in the AA rat line drank significantly more ethanol than the animals with typical ANA pattern, suggesting that this polymorphism might also be relevant in the regulation of voluntary ethanol drinking although it is probably not associated with acetaldehyde metabolism.

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PubMed2002

Effects of ethanol on an acetaldehyde drug discrimination with a conditioned taste aversion procedure.

The current study was designed to investigate whether ethanol shares stimulus properties with acetaldehyde with the use of a discriminative taste aversion procedure. Animals were trained to discriminate a dose of acetaldehyde (0.2 or 0.3 g/kg, i.p.) from saline in eight consecutive cycles consisting of a pairing day (PD) and three nonpairing days (NPDs). On PDs, all animals were injected with a particular dose of acetaldehyde 30 min before a 20-min limited access to a saccharin solution [0.1% (wt./vol.)] and then injected immediately with either LiCl (0.15 M, 1.8 mEq) or saline. On the three following NPDs, animals were injected with saline and 30 min later were presented with the same saccharin solution for 20 min. All animals in each acetaldehyde training dose group acquired discriminative stimulus control before generalization tests were conducted. Results of generalization tests (ethanol doses of 0.8, 1.2, 1.6, and 2.0 g/kg) revealed that ethanol substituted for acetaldehyde at doses of 1.2 and 1.6 g/kg for both training doses of acetaldehyde. The findings for this study indicate that acetaldehyde and ethanol may share some stimulus properties.

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PubMed2002

Acetaldehyde activates Jun/AP-1 expression and DNA binding activity in human oral keratinocytes.

Oral cancer is a significant health problem, particularly among individuals that ingest alcohol in combination with the use of tobacco products. The enhanced development of tobacco-initiated oral cancers by ethanol suggests that ethanol or one of its metabolites may act as a type of tumor promoter. Nevertheless, the mechanisms underlying the ability of ethanol to enhance oral carcinogenesis remain unclear. We hypothesize that acetaldehyde, the first metabolite of ethanol, may activate the expression and/or activity of Jun/AP-1 in oral keratinocytes analogous to the phorbol ester TPA and other tumor promoters in epidermal keratinocytes. To test this hypothesis, we treated HPV immortalized, non-tumorigenic human oral keratinocytes with acetaldehyde at various concentrations and for various times and measured several parameters of Jun/AP-1expression and function. Our results indicated that c-Jun mRNA and protein levels increased in the acetaldehyde treated cells compared to untreated control cells. Moreover, Jun/AP-1 DNA binding activity was rapidly activated by acetaldehyde in a dose-dependent fashion. The increases in Jun protein and AP-1 DNA binding activity were accompanied by increased transactivation of an AP-1 responsive reporter construct as well as increased transcript levels of a candidate AP-1 responsive gene, stromelysin 3. The levels of acetaldehyde employed were minimally toxic to the cells as determined by MTT assays. Thus, acetaldehyde was found to activate the expression and activity of an oncogenic transcription factor in HPV-initiated cells. Taken together, these results suggest that acetaldehyde may participate, at least in part, in the promotion stage of oral carcinogenesis.

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PubMed2006

Modeling of experimental treatment of acetaldehyde-laden air and phenol-containing water using corona discharge technique.

Acetaldehyde-laden air and phenol-contaminated water were experimentally treated using corona discharge reactions and gas absorption in a single water-film column. Mathematical modeling of the combined treatment was developed in this work. Efficient removal of the gaseous acetaldehyde was achieved while the corona discharge reactions produced short-lived species such as O and O- as well as ozone. Direct contact of the radicals and ions with water was known to produce aqueous OH radical, which contributes to the decomposition of organic contaminants: phenol, absorbed acetaldehyde, and intermediate byproducts in the water. The influence of initial phenol concentration ranging from 15 to 50 mg L(-1) and that of influent acetaldehyde ranging from 0 to 200 ppm were experimentally investigated and used to build the math model. The maximum energetic efficiency of TOC, phenol, and acetaldehyde were obtained at 25.6 x 10(-9) mol carbon J(-1), 25.0 x 10(-9) mol phenol J(-1), and 2.0 x 10(-9) mol acetaldehyde J(-1), respectively. The predictions for the decomposition of acetaldehyde, phenol, and their intermediates were found to be in good agreement with the experimental results.

Acetaldehyde↗

PubMed1999

Oxidation of acetaldehyde by peroxynitrite and hydrogen Peroxide/Iron(II). Production Of acetate, formate, and methyl radicals.

Production of free radicals from acetaldehyde oxidation by enzymes and cellular fractions is a well-known process. The toxic effects of acetaldehyde, however, are usually attributed to its reactions with biomolecules to produce adducts. Here, we demonstrate that hypothetical adducts produced from attack of acetaldehyde by two important biological oxidants, peroxynitrite and hydrogen peroxide, decompose to produce acetate, formate, and methyl radicals. Acetate, formate, nitrate, and nitrite were characterized and quantified by capillary electrophoresis. Radicals were detected and quantified by the EPR spectra produced in the presence of spin traps 3, 5-dibromo-4-nitrosobenzenesulfonic acid and 5,5-dimethyl-1-pyrroline N-oxide. Kinetic studies and product analysis were performed at different pHs. The results demonstrate that production of methyl radicals during oxidation of acetaldehyde by hydrogen peroxide was strictly dependent on the presence of iron(II) and occurred via two routes. One involved acetaldehyde attack by the hydroxyl radical to produce the acetyl radical that decomposes to methyl radical and carbon monoxide. The other route involved acetaldehyde attack by deprotonated hydrogen peroxide to produce a hypothetical intermediate that reductively cleaves via the action of present iron(II) to produce radicals. The latter mechanism predominates in the case of peroxynitrite, but radical formation does not require metal ions. Most of the hypothetical adduct produced from acetaldehyde and peroxynitrite (k = 680 M(-)(1) s(-)(1) at pH 7.4 and 37 degrees C) decays to nitrate and regenerates the aldehyde [Uppu, R. M., et al. (1997) Chem. Res. Toxicol. 10, 1331], but about 30% of it produces acetate, formate, and methyl radicals. Part of these oxidized products result from beta-scission and 1,2-shift reactions of the 1-hydroxyethoxyl radical which, together with nitrogen dioxide, freely diffuses from the adduct (20% yields). The results provide yet another example of the metal-independent free radical reactivity of peroxynitrite and may be relevant to the toxic effects associated with heavy drinking and diabetes.

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