dolichols and Alcoholism

The isoprenoid pathway produces three key metabolites--endogenous digoxin (modulate tryptophan/tyrosine transport), dolichol (important in N-glycosylation of proteins), and ubiquinone (free radical scavenger). It was considered pertinent to assess the pathway in alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. In the patient group there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites, as well as reduced endogenous morphine synthesis from tyrosine. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Alcoholic cirrhosis, alcoholic addiction, and acquired hepatocerebral degeneration are associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to NMDA excitotoxicity and altered connective tissue/lipid metabolism important in its pathogenesis. Endogenous morphine deficiency plays a role in alcoholic addiction. The same biochemical patterns were obtained in those with right hemispheric chemical dominance. Alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration occur in right hemispheric, chemically dominant individuals.

Topics: Adult; Alcoholism; Analysis of Variance; Cholesterol; Digoxin; Disease Susceptibility; Dolichols; Dominance, Cerebral; Enzyme Inhibitors; Erythrocytes; Female; Glycoconjugates; Glycosaminoglycans; Hepatolenticular Degeneration; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Liver Cirrhosis, Alcoholic; Male; Membrane Proteins; Neurotransmitter Agents; Polyisoprenyl Phosphates; Sodium-Potassium-Exchanging ATPase; Tryptophan; Tyrosine; Ubiquinone

We report here the comparison of urinary dolichols/creatine (D/Cr) concentration ratios in male non-drinkers, moderate-drinkers and heavy drinkers at admission and during hospitalization, and also discuss its usefulness as a biological marker for alcohol abuse. Urine samples were collected from the following four experimental groups: non-(male and female) and moderate-drinker (male) volunteers, and alcoholic heavy-drinking patients (male) at admission for psychiatric treatment and after 9-15 days hospitalization (informed consent was obtained). Urinary dolichols were determined by high performance liquid chromatography after BondElutC18 (500 mg) extraction. Due to significant differences in urinary D/Cr concentrations between male and female groups in non-drinkers and because the heavy-drinkers available for this study were exclusively male, comparison of the value of urinary D/Cr concentration ratios was subsequently limited to male only. There were no statistical differences in urinary D/Cr concentrations in the male among non-drinkers, moderate-drinkers and heavy-drinkers at admission. The accuracy of urinary D/Cr as a biological marker for alcohol abuse, calculated using the mean +/- 2 s.d. in non- and moderate-drinkers as the normal range, is only 33.3% in heavy-drinkers at admission, while their value of gamma-GTP in serum was 88.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alcohol Drinking; Alcoholism; Biomarkers; Creatinine; Dolichols; Female; Humans; Male; Middle Aged; Predictive Value of Tests

Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the craniofacial dysmorphic features, malformations, and disturbances in growth, neurodevelopment and behavior occurring in individuals prenatally exposed to alcohol. Fetal alcohol syndrome (FAS) represents the severe end of this spectrum. Many pathophysiological mechanisms have hitherto been proposed to account for the disrupted growth and morphogenesis seen in FAS. These include impaired cholesterol-modification of the Sonic hedgehog morphogen, retinoic acid deficiency, lipoperoxidative damage due to alcohol-induced reactive oxygen species combined with reduced antioxidant defences, and malfunctioning cell adhesion molecules. In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) - the most widely used screening tool for congenital disorders of glycosylation (CDG) - was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities. We also present an integrated pathophysiological model of FAS, which incorporates all existing theories mentioned above as well as our novel concept. This model highlights the pivotal role of disrupted isoprenoid metabolism in the origination of FAS.

Topics: Alcohol Drinking; Alcoholism; Antioxidants; Cholesterol; Dolichols; False Positive Reactions; Female; Fetal Alcohol Spectrum Disorders; Glycosylation; Hedgehog Proteins; Humans; Infant; Infant, Newborn; Isoelectric Focusing; Male; Models, Theoretical; Pregnancy; Reactive Oxygen Species; Transferrin; Tretinoin; Vitamin A Deficiency

Previous studies have demonstrated that acute ethanol intoxication affects various steps of protein glycosylation at the level of rat liver endoplasmic reticulum and Golgi apparatus. The aim of this investigation was to demonstrate whether chronic ethanol intake can induce definitive changes of liver glycoprotein processing. Rats were given ethanol by liquid diet for 8 weeks. At the end of this period the triglyceride levels in liver homogenate and microsomes were significantly higher than in controls. Isolated hepatocytes prelabelled with [3H]Na palmitate and [14C]glucosamine showed a significant storage of the lipid and carbohydrate radioactivity in microsomes and Golgi apparatus and a significant impairment of labelled glycolipoprotein secretion. Changes of the glycosylation steps were observed both in endoplasmic reticulum and in Golgi apparatus: in the former the levels of dolichyl phosphate, which is rate-limiting for the synthesis of glycoprotein, showed a significant reduction; in the latter the activity of the main enzymes responsible for the terminal glycosylation process was significantly decreased. These data suggest that an impairment of glycoprotein maturation may be involved in the pathogenesis of liver injury induced by chronic ethanol intake.

Topics: Alcoholism; Animals; Dolichol Phosphates; Dolichols; Ethanol; Fatty Liver, Alcoholic; Female; Glucosamine; Glycoproteins; Golgi Apparatus; Liver; Membrane Glycoproteins; Microsomes, Liver; Palmitic Acid; Palmitic Acids; Rats; Rats, Sprague-Dawley; Triglycerides

This report describes the quantitation of urinary dolichols (Dolichol-90, -95 and -100) by advanced high performance liquid chromatography (HPLC) after BondElutC18 (500 mg) cartridge column extraction. The urine sample (15 ml) mixed with heneicosaprenol as internal standard (IS, 300 ng) was adjusted to pH 3 by 0.1N hydrochloric acid (HCl). BondElutC18 (500 mg) column was preactivated by methanol (4 ml) and distilled water (4 ml), and the urine sample was applied. The column was washed by HCl-sodium acetate buffer (pH 3, 6 ml), distilled water (4 ml) and methanol (4 ml), and then eluted by 2-propanol/dichloromethane/methanol (5/3/2 by vol, 4 ml). After drying the eluted solution under nitrogen gas flow, the residue was dissolved in 60 microliters of HPLC mobile phase, and 20 microliters of the mixture was injected into the HPLC. The HPLC conditions were as follows: column, mu Bondapack C18 (Waters); mobile phase, 2-propanol/methanol (72/28 by vol), 1.0 ml/min; detection, UV at 210 nm. Recovery yields of Dolichol-90, -95 and -100 were in the range of 68-75% and the calibration curve of each dolichol was linear over the range 0.01-1.00 micrograms.

Topics: Alcoholism; Biomarkers; Chromatography, High Pressure Liquid; Dolichols; Humans; Sensitivity and Specificity

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.

Topics: Alcohol Drinking; Alcoholic Intoxication; Alcoholism; Dolichols; Ethanol; Female; Humans; Ill-Housed Persons; Male; Middle Aged; Temperance

To study the activities of serum gamma-glutamyltransferase (GGT), aspartate and alanine aminotransferases (AST, ALT), and their ratio (AST/ALT), mean erythrocyte cell volume (MCV) and urinary dolichol output in alcohol-abusing pregnant women, and compare the results to those of abstinent pregnant women.. Prospective descriptive study.. Special outpatient clinic for pregnant problem-drinkers in the department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Finland.. 25 pregnant women referred to the special clinic at between 12 and 24 weeks gestation, they consumed at least 150 g of ethanol weekly, and a control group of 20 abstinent pregnant women matched for age, parity and smoking habits.. The women were encouraged to visit the clinic at 2-4 week intervals. At each visit blood and urine samples were obtained, and the women were interviewed on their alcohol consumption during the previous weeks and encouraged to abstain in the future.. Neonatal condition, fetal alcohol effects (FAE) in the newborn. Serum activities of GGT, AST and ALT, the AST/ALT ratio, the MCV, and the urinary concentration of dolichol in alcohol-abusing women with either healthy or FAE infants, compared with those of abstinent women with healthy infants.. Of the 25 alcohol-abusing women 13 gave birth to infants with FAE and 12 to healthy infants. All the women in the control group gave birth to healthy infants. GGT, AST and ALT activities were increased in all alcohol-abusing women, regardless whether the infant had FAE or not. GGT was the best of these markers, GGT activities above the 95th normal centile were found in 33% of the samples from all alcohol-abusing women. The AST/ALT ratio, MCV and urinary dolichol concentration were poor indicators of abusive drinking.. Maternal alcohol abuse is difficult to assess by laboratory tests. Of the commonly used and easily available tests, GGT proved to be the best in our study.

Topics: Adult; Alanine Transaminase; Alcoholism; Aspartate Aminotransferases; Dolichols; Erythrocyte Indices; Female; Fetal Alcohol Spectrum Disorders; gamma-Glutamyltransferase; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Prospective Studies

The purpose of this study was to replicate the results of Pullarkat and Raguthu and Roine et al. who found elevated levels of urinary dolichol (long-chain 2,3-dihydropolyprenols) in chronic alcoholic patients. We investigated a sample of 21 alcohol-dependent inpatients voluntarily entering detoxification treatment. Urinary dolichol was only slightly increased as compared to 21 healthy controls. When dolichol was related to urinary creatinine no differences between alcoholic patients and controls could be found. Under conditions of confirmed abstinence the slightly elevated levels of dolichol returned to normal within 2 weeks. Compared with the sensitivity of gamma-glutamyltransferase which ranges from 72-85%, the value of urinary dolichol (sensitivity 9-19%) as a biochemical marker of alcoholism must be doubted.

Topics: Adult; Alcoholism; Creatinine; Dolichols; Ethanol; Female; gamma-Glutamyltransferase; Humans; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged

Cerebral gray and white matter and liver dolichol levels were measured in postmortem samples from chronic alcoholics and nonalcoholic controls following recent suggestions that dolichol levels may be used as a marker for alcoholism. No significant differences in brain dolichol were found between the control and alcoholic groups. A significant reduction in the liver dolichol was observed in the alcoholic group. This was most marked in those alcoholics with liver disease.

Topics: Adult; Aged; Alcoholism; Brain; Dolichols; Fatty Liver, Alcoholic; Female; Humans; Liver; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Parietal Lobe

Serum dolichol levels were studied in 95 active alcoholics and 16 abstinent alcoholics (at the time of blood sampling) and compared to those of 41 social drinkers. Active alcoholics had a significantly higher mean serum dolichol concentration (182.7 +/- 5.1 ng/ml, p less than 0.001 than either abstinent alcoholics (138.7 +/- 5.4 ng/ml) or social drinkers (142.1 +/- 4.1 ng/ml). During weekend (48 hr) heavy drinking (5.5 g of alcohol per kg b.w.) no significant changes were seen in mean serum dolichol concentrations in 10 healthy, nonalcoholic volunteers. Neither did moderate drinking for 10 days (60 g of alcohol daily)--preceded and followed by a period of abstinence--produce any significant changes in serum dolichol levels in 10 nonalcoholic subjects. During detoxification treatment of 12 alcoholics, mean serum dolichol concentration stayed constant for the first 7 days; on entering treatment it was 227.7 +/- 15.0 ng/ml, on the 3rd day 238.5 +/- 15.9 ng/ml, and on the 7th day of treatment 222.6 +/- 18.6 ng/ml. Our results show that as well as increasing urinary dolichol excretion, chronic alcohol abuse also produces increased serum dolichol concentrations. However, contrary to urinary dolichols, serum dolichol levels do not react significantly to heavy drinking lasting for 48 hr in nonalcoholic volunteers. Furthermore in alcoholics increased serum dolichol concentrations do not decrease as rapidly during abstinence as urinary dolichol concentrations do.

Topics: Adult; Alcohol Drinking; Alcoholic Intoxication; Alcoholism; Dolichols; Ethanol; Female; Follow-Up Studies; Humans; Liver Function Tests; Male; Middle Aged; Temperance

Urinary dolichol levels of 31 skid-row alcoholics and 49 alcoholics entering a detoxification unit were compared to those of 51 nonalcoholic controls (social drinkers). The mean urinary dolichol content as related to urinary creatinine was significantly (p less than 0.001) higher in the two groups of alcoholics than in the controls. In this material the sensitivity of increased urinary dolichol in the detection of alcoholism was 68% as compared to 44% sensitivity of serum gamma-glutamyltransferase. The percentage of false-positives in the control group was 3.9%. Urinary dolichol is suggested as a potential tool for the detection and follow-up of alcohol abuse.

Topics: Adult; Aged; Alcoholism; Diterpenes; Dolichols; Female; Humans; Male; Middle Aged; Transferases

Topics: Acetates; Alcoholism; Diterpenes; Dolichols; Ethanol; Humans; Liver; Metabolic Clearance Rate

A reversed-phase "high-performance" liquid chromatographic assay for dolichols-18, -19 and -20 in urine is described. Dolichols are extracted from urine by using C18 cartridges and are chromatographed with a mobile phase consisting of 2-propanol/methanol, the effluent being monitored at 210 nm. The useful lower limit of sensitivity for quantification is 4 pmol (5 ng) of each dolichol per 5-microL injection, corresponding to 1.6 nmol (2 ng) per liter of urine. Heneicosaprenol is satisfactory as the internal standard. Peak heights and the amounts of dolichols applied to the column are linearly related from 4 to 110 pmol. Mean analytical recovery was 71%. For three different concentrations the mean within-assay CV was 6.4%, the between-assay CV 11%. The normal reference interval of total dolichols found for healthy adults was 17-101 micrograms/24 h (n = 30) or 1.9-11 micrograms per millimole of creatinine (n = 39). I determined the distribution of the main dolichols in urine and applied the assay also for samples from alcoholics.

Topics: Adult; Alcoholism; Chromatography, High Pressure Liquid; Creatinine; Diterpenes; Dolichols; Humans; Reference Standards; Reference Values