• Energy Research

Alcohol appears to affect dolichol metabolism, as both serum and urinary dolichol concentrations were found to be significantly higher in alcoholics than in social drinkers. Furthermore, acute heavy drinking (5.5 g alcohol/kg body weight during 42 h) increased urinary dolichol excretion significantly, whereas moderate drinking (60 g/day for 10 days) had no effect. Increased urinary dolichol concentrations in alcoholics returned rapidly to normal with a half-life decay of 3 days, whereas increased serum dolichol concentrations did not change during a 7-day observation period. The mechanism behind alcohol-induced alterations in dolichol metabolism remains unclear, but based on our results, it seems likely that serum and urinary dolichols are regulated independently from each other.Key words: polyprenols, biological membranes, substance abuse, lysosomes.

AbstractAcetaldehyde is a highly toxic and mutagenic product of alcohol fermentation and metabolism which has been classified as a Class I carcinogen for humans by the International Agency for Research on Cancer of the World Health Organisation (WHO). Many Candida species representing oral microbiota have been shown to be capable of marked acetaldehyde production. The aim of our study was to examine the effects of various sugar alcohols and sugars on microbial acetaldehyde production. The study hypothesis was that xylitol could reduce the amount of acetaldehyde produced by Candida. Laboratory and clinical isolates of seven Candida species were selected for the study. The isolates were incubated in 12 mM ethanol and 110 mM glucose, fructose or xylitol at 37°C for 30 min and the formed acetaldehyde was measured by gas chromatography. Xylitol significantly (p < 0.0001) reduced the amount of acetaldehyde produced from ethanol by 84%. In the absence of xylitol, the mean acetaldehyde production in ethanol incubation was 220.5 μM and in ethanol–xylitol incubation 32.8 μM. This was found to be mediated by inhibition of the alcohol dehydrogenase enzyme activity. Coincubation with glucose reduced the amount of produced acetaldehyde by 23% and coincubation with fructose by 29%. At concentrations that are representative of those found in the oral cavity during the intake of proprietary xylitol products, xylitol was found to reduce the production of carcinogenic acetaldehyde from ethanol by Candida below the mutagenic level of 40–100 μM.

Ingested ethanol is transported to the colon via blood circulation, and intracolonic ethanol levels are equal to those of the blood ethanol levels. In the large intestine, ethanol is oxidized by colonic bacteria, and this can lead to extraordinarily high acetaldehyde levels that might be responsible, in part, for ethanol‐associated carcinogenicity and gastrointestinal symptoms. It is believed that bacterial acetaldehyde formation is mediated via microbial alcohol dehydrogenases (ADHs). However, almost all cytochrome‐containing aerobic and facultative anaerobic bacteria possess catalase activity, and catalase can, in the presence of hydrogen peroxide (H2O2, use several alcohols (e.g., ethanol) as substrates and convert them to their corresponding aldehydes. In this study we demonstrate acetaldehyde production from ethanol in vitro by colonic contents in a reaction catalyzed by both bacterial ADH and catalase. The amount of acetaldehyde produced by the human colonic contents was proportional to the ethanol concentration, the amount of colonic contents, and the length of incubation time, even in the absence of added nicotinamide adenine dinucleotide or H2O2. The catalase inhibitors sodium azide and 3‐amino‐1,2,4‐triazole (3‐AT) markedly reduced the amount of acetaldehyde produced from 22 mM ethanol in a concentration dependent manner compared with the control samples (0.1 mM sodium azide to 73% and 10 mM 3‐AT to 67% of control). H202 generating system [β‐D(+)‐glucose + glucose oxidase] and nicotinamide adenine dinucleotide induced acetaldehyde formation up to 6‐ and 5‐fold, respectively, and together these increased acetaldehyde formation up to 11‐fold. The mean supernatant catalase activity was 0.53 ± 0.1 jumol/min/mg protein after the addition of 10 mM H202, and there was a significant (p < 0.05) correlation between catalase activity and acetaldehyde production after the addition of the hydrogen peroxide generating system. Our results demonstrate that colonic contents possess catalase activity, which probably is of bacterial origin, and indicate that in addition to ADH, part of the acetaldehyde produced in the large intestine during ethanol metabolism can be catalase dependent.

We analyzed the blood alcohol and acetaldehyde concentrations in nine alcoholics and four healthy nonalcoholic controls during and after an intravenous infusion of a high and a low dose of alcohol. In the alcoholics, the mean rates of plasma ethanol disappearance were significantly higher than in nonalcoholic controls. In the control subjects, the blood acetaldehyde levels were, in general, below the detection limit (<0.5 #μm), but in sharp contrast to this, an elevated blood acetaldehyde during ethanol infusion was found in 6/9 alcoholics. Peak blood acetaldehyde values were higher after the high than the low dose of alcohol. Fructose infusion significantly enhanced the rate of plasma ethanol disappearance both in controls and in alcoholics, and this was usually associated with a significant elevation of blood acetaldehyde level. The maximal specific activities (expressed as milliunits/mg of protein) of alcohol, lactate, and aldehyde dehydrogenases in liver were significantly lower in alcoholics than in controls. Even more importantly, the peak blood acetaldehyde correlated negatively with the activity of hepatic “low‐Km” aldehyde dehydrogenase. Our results suggest that the main reason for blood acetaldehyde elevation seen in these chronic alcoholics is their impaired capacity to metabolize acetaldehyde. This may be further accentuated by the increased rate of ethanol oxidation.

Ethanol is neither genotoxic nor mutagenic. Its first metabolite acetaldehyde, however, is a powerful local carcinogen. Point mutation in ALDH2 gene proves the causal relationship between acetaldehyde and upper digestive tract cancer in humans. Salivary acetaldehyde concentration and exposure time are the two major and quantifiable factors regulating the degree of local acetaldehyde exposure in the ideal target organ, oropharynx. Instant microbial acetaldehyde formation from alcohol represents >70% of total ethanol associated acetaldehyde exposure in the mouth. In the oropharynx and achlorhydric stomach acetaldehyde is not metabolized to safe products, instead in the presence of alcohol it accumulates in saliva and gastric juice in mutagenic concentrations. A common denominator in alcohol, tobacco and food associated upper digestive tract carcinogenesis is acetaldehyde. Epidemiological studies on upper GI tract cancer are biased, since they miss information on acetaldehyde exposure derived from alcohol and acetaldehyde present in 'non-alcoholic' beverages and food.

In industrialized countries alcohol and tobacco are the main risk factors of upper digestive tract cancer. With regard to the pathogenesis of these cancers, there is strong epidemiological, biochemical and genetic evidence supporting the role of the first metabolite of alcohol oxidation--acetaldehyde--as a common denominator. Alcohol is metabolized to acetaldehyde locally in the oral cavity by microbes representing normal oral flora. Poor oral hygiene, heavy drinking and chronic smoking modify oral flora to produce more acetaldehyde from ingested alcohol. Also, tobacco smoke contains acetaldehyde, which during smoking becomes dissolved in saliva. Via swallowing, salivary acetaldehyde of either origin is distributed from oral cavity to pharynx, oesophagus and stomach. Strongest evidence for the local carcinogenic action of acetaldehyde provides studies with ALDH2-deficient Asian drinkers, who form an exceptional human model for long-term acetaldehyde exposure. After drinking alcohol they have an increased concentration of acetaldehyde in their saliva and this is associated with over 10-fold risk of upper digestive tract cancers. In conclusion, acetaldehyde derived either from ethanol or tobacco appears to act in the upper digestive tract as a local carcinogen in a dose-dependent and synergistic way.

Studies in our laboratory have revealed that Helicobacter pylori exhibits significant cytosolic alcohol dehydrogenase activity and that the enzyme is fully active at ethanol concentrations prevailing in the stomach during alcohol consumption or after alcohol is completely absorbed from the stomach and is available through blood circulation only. Moreover, even the low levels of endogenous ethanol found in the stomach can be oxidized to acetaldehyde by H. pylori alcohol dehydrogenase. The metabolic significance of the enzyme remains as yet unresolved. Under microaerobic conditions, however, the enzyme could be of importance in the energy metabolism of the organism. In the presence of excess ethanol, H. pylori alcohol dehydrogenase produces significant amounts of acetaldehyde. Acetaldehyde is a toxic and reactive compound and could theoretically be a pathogenetic factor in H. pylori-associated gastric injury. Preliminary studies have indicated that acetaldehyde inhibits gastric mucosal regeneration and forms stable adducts with mucosal proteins. Both of these mechanisms could cause gastric injury. The role of H. pylori-related acetaldehyde formation in vivo, however, needs to be established in future studies. In antral human gastric mucosa, H. pylori infection is associated with a significant decrease in alcohol dehydrogenase activity. Similarly, in specific pathogen-free mice with a prolonged infection, gastric alcohol dehydrogenase activity is decreased; however, this is not clearly reflected in the bioavailability of ethanol or the amount of its first pass metabolism.

Abstract In isolated hepatocytes, 6–50 mM ethanol inhibited the incorporation of amino acids into protein. These in vitro effects of ethanol were associated with greater increases in lactate/pyruvate ratios, slower rates of ethanol oxidation, and smaller acetaldehyde concentrations than those found in vivo. When the redox changes produced by ethanol were decreased by the addition of 4-methylpyrazole (an inhibitor of alcohol dehydrogenase), methylene blue (a scavenger of reducing equivalents) or a combination of aspartate and α-ketoglutarate (which provides substrates for the translocation of reducing equivalents from the cytosol into the mitochondria), the ethanol-induced inhibition of protein synthesis was prevented. This effect took place despite marked elevations of the acetaldehyde concentration after the addition of either methylene blue or aspartate plus α-ketoglutarate. When hepatocytes were isolated from rats fed alcohol-containing diets and incubated with ethanol, the redox changes were attenuated and ethanol failed to inhibit protein synthesis. Acute ethanol administration to rats decreased secretion of newly synthesized albumin with retention of albumin in the liver. This acute effect of ethanol on secretion was not associated with impairment of the synthesis of either albumin or total liver protein, as determined in vivo by the incorporation of [ 14 C]leucine into proteins and the specific activity of leucyl-tRNA. Thus, acute ethanol administration inhibits hepatic protein secretion rather than protein synthesis. The inhibitory effect on protein synthesis produced by ethanol in vitro reflects the inability of isolated liver preparations to handle the excess of reducing equivalents generated by ethanol oxidation and does not correlate with acetaldehyde concentrations. The in vivo relevance of these in vitro effects remains to be determined.