4-hydroxy-2-nonenal and Alcoholism

The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied.. We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes.. Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4-hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization-tandem mass spectrometry.. The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 ± 8.0 ng/mL versus 35.4 ± 2.3 ng/mL; p < .001; HHE 40.1 ± 6.7 ng/mL versus 17.7 ± 4.1 ng/mL; p < .001; MDA 80.0 ± 7.2 ng/mL versus 40.9 ± 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= -0.428, -0.388, -0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ.. Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge.

Topics: Activation, Metabolic; Alcoholism; Aldehydes; Biomarkers; Cysteine Proteinase Inhibitors; Female; Follow-Up Studies; Humans; Lipid Peroxidation; Male; Methanol; Middle Aged

Alcoholic liver disease (ALD) is a type of chronic liver disease caused by long-term heavy ethanol consumption. Danshen is one of the most commonly used substances in traditional Chinese medicine and has been widely used for the treatment of various diseases, and most frequently, the ALD. The current study aims to determine the potential beneficial effect of Danshen administration on ALD and to clarify the underlying molecular mechanisms. Danshen administration improved liver pathologies of ALD, attenuated alcohol-induced increment of hepatic 4-Hydroxynonenal (4-HNE) formation, and prevented hepatic Peroxisome proliferators activated receptor alpha (PPARα) suppression in response to chronic alcohol consumption. Cell culture studies revealed that both hepatoprotective effect and increased intracellular 4-HNE clearance instigated by Danshen supplementation are PPARα-dependent. In conclusion, Danshen administration can protect against ALD via inducing PPARα activation and subsequent 4-HNE degradation.

Topics: Alcoholism; Aldehydes; Animals; Cell Death; Dietary Supplements; Drugs, Chinese Herbal; Ethanol; Hep G2 Cells; Hepatocytes; Humans; Liver; Liver Diseases, Alcoholic; Male; Mice, Inbred C57BL; Phytotherapy; PPAR alpha; Protective Agents; Salvia miltiorrhiza; Triglycerides

In this study, we present the novel findings that chronic ethanol consumption induces mitochondrial protein hyperacetylation in the kidney and correlates with significantly increased renal oxidative stress. A major proteomic footprint of alcoholic liver disease (ALD) is an increase in hepatic mitochondrial protein acetylation. Protein hyperacetylation has been shown to alter enzymatic function of numerous proteins and plays a role in regulating metabolic processes. Renal mitochondrial targets of hyperacetylation include numerous metabolic and antioxidant pathways, such as lipid metabolism, oxidative phosphorylation, and amino acid metabolism, as well as glutathione and thioredoxin pathways. Disruption of protein lysine acetylation has the potential to impair renal function through metabolic dysregulation and decreased antioxidant capacity. Due to a significant elevation in ethanol-mediated renal oxidative stress, we highlight the acetylation of superoxide dismutase, peroxiredoxins, glutathione reductase, and glutathione transferase enzymes. Since oxidative stress is a known factor in ethanol-induced nephrotoxicity, we examined biochemical markers of protein hyperacetylation and oxidative stress. Our results demonstrate increased protein acetylation concurrent with depleted glutathione, altered Cys redox potential, and the presence of 4-HNE protein modifications in our 6-week model of early-stage alcoholic nephrotoxicity. These findings support the hypothesis that ethanol metabolism causes an influx of mitochondrial metabolic substrate, resulting in mitochondrial protein hyperacetylation with the potential to impact mitochondrial metabolic and antioxidant processes.

Topics: Acetylation; Alcoholism; Aldehydes; Amino Acid Sequence; Amino Acids; Animals; Ethanol; Glutathione; Glutathione Reductase; Glutathione Transferase; Kidney; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Molecular Sequence Data; Oxidative Phosphorylation; Oxidative Stress; Peroxiredoxins; Superoxide Dismutase

Excessive alcohol consumption is a common cause for upper gastrointestinal tract cancers. However, the primary mechanisms of alcohol-induced carcinogenesis have remained poorly defined.. We examined the generation and subcellular distribution of protein adducts with acetaldehyde (AA), the first metabolite of ethanol, and end products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), from oral biopsy specimens obtained from 36 subjects (11 British, 25 Japanese) reporting alcohol misuse. All patients had been diagnosed with oral pre-cancer (leukoplakia, n = 7) or squamous cell carcinoma (SCC; n = 29). Automated immunostaining for AA, MDA and HNE adducts was performed using monospecific antibodies.. Positive staining for AA, MDA and HNE adducts was observed in the dysplastic or malignant epithelial cells, HNE being relatively the most abundant adduct species. The subgroup of Japanese patients had higher levels of AA and MDA, although not HNE, than the British sample. When the material was divided to those with SCC or leukoplakia, MDA adducts but not the other antigens were more prominent in the former group. Significant correlations were found between the different adducts (AA vs. MDA, r = 0.68, P < 0.001; AA vs. HNE, r = 0.47, P < 0.01 and MDA vs. HNE, r = 0.59, P < 0.001). In addition, cytochrome P450 2E1 staining was found in these samples, correlating with both AA and MDA adducts.. The data indicates that AA- and lipid peroxidation-derived adducts are formed in oral tissues of alcohol misusers with oral leukoplakia and cancer. The findings also support a pathogenic role of AA and excessive oxidative stress in carcinogenesis.

Topics: Acetaldehyde; Alcoholism; Aldehydes; Carcinoma, Squamous Cell; Cytochrome P-450 CYP2E1; Ethanol; Female; Humans; Immunohistochemistry; Japan; Leukoplakia, Oral; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Mouth Neoplasms; Oxidative Stress; Protein Binding; United Kingdom

The aim of the study was the estimation of intensity of lipid peroxidation in alcohol dependent male patients after three months of therapy with naltrexone or tianeptine and the next three months follow-up. 61 males with clinical diagnosis of alcohol dependence (ICD-10) have been examined. The investigated parameters have been determined in blood serum, the 8-iso-prostaglandin F2 alpha by means of immunoenzymatic assay (ELISA) and malondialdehyde with 4-hydroxynonenal by means of colorimetric method. In alcohol dependent men before pharmacotherapy the mean concentration of 8-iso-PGF2 alpha and [MDA + 4-HNE] was higher than the reference interval. Both, after three months of applied drugs and the next three months follow-up, the concentration of studied parameters decreased considerably. The above results show intensification of lipid peroxidation in alcohol abusers and advantageous influence of abstinence from alcohol and treatment of naltrexone or tianeptine on free-radical changes of lipids as well.

Topics: Adult; Alcoholism; Aldehydes; Antidepressive Agents, Tricyclic; Dinoprost; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; F2-Isoprostanes; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Naltrexone; Narcotic Antagonists; Thiazepines; Time Factors

Oxidative stress is considered to be a forerunner of pancreatitis. Since we had found polyenylphosphatidylcholine, a mixture of polyunsaturated phosphatidylcholines extracted from soybeans, to protect against hepatic oxidative stress, we now tested its effects on the pancreas. Sprague-Dawley rats were pair-fed for two months nutritionally adequate liquid diet containing ethanol (36% of energy) or isocaloric carbohydrate, with either polyenylphosphatidylcholine (3 g/1000 kcal) or safflower oil, with or without 5 g/1000 kcal carbonyl iron. Parameters of oxidative stress (F2-isoprostanes, 4-hydroxynonenal, reduced glutathione), ubiquinol-10, ubiquinol-9 and vitamin E, as well as phosphatidylcholine species, were assessed by GC/MS and/or HPLC. Alcohol feeding increased pancreatic 4-hydroxynonenal three-fold, F2-isoprostanes and ubiquinol-9 by more than 70%, whereas it decreased total phospholipids, several phosphatidylcholine species, ubiquinol-10 and glutathione, especially in iron fed rats. Polyenylphosphatidylcholine prevented the rise in 4-hydroxynonenal and F2-isoprostanes, the decrease in dilinoleoylphosphatidylcholine and oleoyllinoleoylphosphatidylcholine and opposed the alcohol-induced decrease of glutathione; alpha-tocopherol remained unchanged. Iron had no significant effect except for decreasing ubiquinol-10 in the pancreas and increasing aminotransferases in the plasma. Thus, the alcohol-induced oxidative stress in the pancreas was shown to be prevented by polyenylphosphatidylcholine which may act, in part, by correcting the depletion of several phosphatidylcholine species.

Topics: Alcoholism; Aldehydes; Animals; Chromatography, High Pressure Liquid; Diet; Dietary Supplements; Dinoprost; Ethanol; Gas Chromatography-Mass Spectrometry; Glutathione Disulfide; Glycine max; Iron; Lipid Peroxidation; Oxidative Stress; Pancreas; Phosphatidylcholines; Rats; Rats, Sprague-Dawley; Safflower Oil