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Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption.sup.1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers.sup.1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer.sup.3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells.sup.5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision--analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions--instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism. DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism., Author(s): Michael R. Hodskinson [sup.1] , Alice Bolner [sup.2] , Koichi Sato [sup.2] , Ashley N. Kamimae-Lanning [sup.1] , Koos Rooijers [sup.2] , Merlijn Witte [sup.2] , Mohan Mahesh [sup.1] [...]

The duration and extent of the body's exposure to beverage alcohol (i.e., ethanol) is the primary determinant of ethanol's pleiotropic effects on human health (Edenberg 2007). The time course of [...]

Alcohol metabolism's various processes create harmful compounds that contribute to cell and tissue damage. In particular, the enzyme cytochrome P450 2E1 (CYP2E1) plays a role in creating a harmful condition [...]

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many behavioral effects of ethanol. However, its precise role remains a matter of debate, with some researchers suggesting that acetaldehyde has no role in the effects of ethanol and others contending that ethanol is a pro-drug whose pharmacological action is mediated by acetaldehyde. Recent studies support a role for acetaldehyde in the stimulant, reinforcing, hypnotic and amnesic effects of ethanol, and, in particular, alcohol abuse and alcoholism. However, current evidence indicates that acetaldehyde is not involved in some of the major neurochemical effects of ethanol. It is therefore likely that ethanol and acetaldehyde molecules act synergistically to determine the multiple neurochemical and behavioral effects of alcohol consumption.

The respiratory inhibitor cyanide stimulates growth of the ethanologenic bacterium Zymomonas mobilis, perhaps by diverting reducing equivalents from respiration to ethanol synthesis, thereby minimizing accumulation of toxic acetaldehyde. This study sought to identify cyanide-sensitive components of respiration. In aerobically grown, permeabilized Z. mobilis cells, addition of 200 [micro]M cyanide caused gradual inhibition of ADH II, the iron-containing alcohol dehydrogenase isoenzyme, which, in aerobic cultures, might be oxidizing ethanol and supplying NADH to the respiratory chain. In membrane preparations, NADH oxidase was inhibited more rapidly, but to a lesser extent, than ADH II. The time-course of inhibition of whole-cell respiration resembled that of NADH oxidase, yet the inhibition was almost complete, and was accompanied by an increase of intracellular NADH concentration. Cyanide did not significantly affect the activity of ADH I, the zinc-containing alcohol dehydrogenase isoenzyme. When an aerobic batch culture was grown in the presence of 200 [micro]M cyanide, cyanide-resistant ADH II activity was observed, its appearance correlating with the onset of respiration. It is concluded that the membrane-associated respiratory chain, but not ADH II, is responsible for the whole-cell cyanide sensitivity, while the cyanide-resistant ADH II is needed for respiration in the presence of cyanide, and represents an adaptive response of Z. mobilis to cyanide, analogous to the induction of alternative terminal oxidases in other bacteria.

The crystal structure of the bifunctional enzyme 4-hydroxy-2-ketovalerate aldolase (DmpG)/acylating acetaldehyde dehydrogenase (DmpF), which is involved in the bacterial degradation of toxic aromatic compounds, has been determined by multiwavelength anomalous dispersion (MAD) techniques and refined to 1.7-[Angstrom] resolution. Structures of the two polypeptides represent a previously unrecognized subclass of metal-dependent aldolases, and of a CoA-dependent dehydrogenase. The structure reveals a mixed state of [NAD.sup.+] binding to the DmpF protomer. Domain movements associated with cofactor binding in the DmpF protomer may be correlated with channeling and activity at the DmpG protomer. In the presence of [NAD.sup.+] a 29-[Angstrom]-long sequestered tunnel links the two active sites. Two barriers are visible along the tunnel and suggest control points for the movement of the reactive and volatile acetaldehyde intermediate between the two active sites.

Research has been conducted on yogurt bacterium Streptococcus thermophilus. The role of serine hydroxymethyltransferase in production of acetaldehyde by this bacterium has been investigated, and the results demonstrate that it is possible to control and improve acetaldehyde production in fermented products with S. thermophilus as starter culture.

Research has been conducted on the 3-oxa-tocopherol-type stabilizer, 2,4,5,7,8-pentamethyl-4H-1,3-benzodioxin-6-ol. The oxidation behavior of this compound has been investigated and the details are reported.

Objective: Acetaldehyde (ACH) has been shown to have aversive or reinforcing actions in relation to ethanol consumption. We have previously observed that a pharmacological dose of AcH (50-150 mg/kg) administered intraperitoneally (i.p.) produced a dose-dependent flavor aversion in low-ethanol drinker (UChA) rats, whereas high-ethanol drinker (UChB) rats appeared to be insensitive to AcH. Both strains of rats differ innately in their brain aldehyde dehydrogenase (ALDH) activity and in their capacity to develop acute tolerance to ethanol. The present study evaluates the effects of AcH, in UChA and UChB rats, on rats' behavior, their voluntary ethanol consumption and the development of acute functional tolerance to motor impairment induced by a dose of ethanol. Method: Subjects were rats selectively bred for high (UChB; n = 48) and low (UChA; n = 40) voluntary ethanol consumption. Rats were treated with either saline or doses of AcH (50 or 100 mg/kg, i.p.), and examined for effects on motor activity, on voluntary alcohol consumption with free access to a 10% alcohol solution and on acute tolerance to motor impairment induced by an ethanol dose (2.3 g/kg, i.p.), using the tilting plane test. Results: AcH, 50 or 100 mg/ kg, caused a dose-dependent loss of the righting reflex in UChA rats, whereas in UChB rats with same dose, a slight excitement was observed. There was significant increase of voluntary ethanol consumption in UChB rats (p < .001) 17 hours after the AcH injection, compared with saline-treated and control rats; in UChA rats, no change in voluntary ethanol consumption was produced. AcH produced a faster acute tolerance-to-ethanol development in UChB rats (p < .001) as compared with saline-treated and control rats, and no change in acute tolerance in UChA rats. Acetaldehyde injection did not change total mitochondrial ALDH2 activity. Conclusions: These results, show that, 17 hours later, treatment of rats with pharmacological doses of acetaldehyde alters the voluntary ethanol consumption and acute tolerance development in UChB but not UChA rats. One of the factors involved may be a different sensitivity to AcH in these rat strains., A CETALDEHYDE, the reactive metabolite of ethanol, has been shown to display various actions in relation to ethanol consumption. Elevated blood acetaldehyde (ACH) concentrations are generally considered aversive and are [...]

Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular [Ca.sup.2+] properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular [Ca.sup.2+] in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular [Ca.sup.2+] was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy. transgene; acetaldehyde; shortening; intracellular calcium ion transient