Alcohol
Volume 38, Issue 1 , Pages 37-43, January 2006

Saturation of retinol-binding protein correlates closely to the severity of alcohol-induced liver disease

  • Sabine Wagnerberger

      Affiliations

    • Department of Physiology of Nutrition and Gender Research, Hohenheim University (140e), Garbenstrasse 28, 70599 Stuttgart, Germany
    • ,
  • Christian Schäfer

      Affiliations

    • Department of Gastroenterology and Hepatology, Robert-Bosch-Hospital, 70341 Stuttgart, Germany
    • ,
  • Christiane Bode

      Affiliations

    • Department of Physiology of Nutrition and Gender Research, Hohenheim University (140e), Garbenstrasse 28, 70599 Stuttgart, Germany
    • ,
  • Alexandr Parlesak

      Affiliations

    • Department of Physiology of Nutrition and Gender Research, Hohenheim University (140e), Garbenstrasse 28, 70599 Stuttgart, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49-711-4594184; fax: +49-711-4593947.

Received 22 February 2006; received in revised form 29 March 2006; accepted 31 March 2006.

Article Outline

Abstract 

Impaired metabolism of retinol has been shown to occur in alcohol-induced liver disease (ALD). The purpose of the present study was to investigate the saturation of retinol-binding protein (RBP) in 6 patients with different stages of ALD. Hospitalized alcohol consumers (n=118) with different stages of ALD (ALD1: mild stage of liver damage; ALD2: moderately severe changes of the liver with signs of hepatic inflammation; ALD3: severely impaired liver function) and 45 healthy control subjects were nutritionally assessed, and retinol and RBP content was measured in plasma by high-performance liquid chromatography and enzyme-linked immunosorbent assay methods, respectively. No differences were noted in daily retinol intake, but subjects with ALD had significantly lower concentrations of retinol in plasma (ALD1: 1.81±0.17μmol/l [mean±S.E.M.]; ALD2: 1.95±0.24μmol/l; ALD3: 0.67±0.13μmol/l) compared to controls (2.76±0.19μmol/l). Subjects of group ALD2 had significantly higher plasma RBP levels than controls (P<.05) and patients with ALD1 (P<.05) and ALD3 (P<.001). The relative saturation of RBP with retinol decreased with severity of ALD (controls: 76.8±5.0%; ALD1: 55.8±6.5%; ALD2: 43.5±6.2%; ALD3: 29.0±5.1%). The present study indicates that plasma concentrations of retinol and RBP per se do not correlate to severity of ALD, but rather that the retinol/RBP ratio links to the severity of alcohol-induced liver damage. From these results, a reduced availability of retinol in the periphery due to an altered saturation of RBP can be concluded.

Keywords: Retinol, Retinol-binding protein, Alcohol-induced liver disease

 

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1. Introduction 

Considering the high number of people dying as a consequence of alcohol abuse (about 3.6% of all cases of death in 1993 in Germany) (Feuerlein, 1996), chronic alcohol consumption is an important health problem in industrialized countries. Earlier studies demonstrate the existence of a dose–response relation between alcohol intake and the risk of liver disease (Day, 1997, Lieber, 1994). As a consequence of alcohol abuse, different alcohol-induced liver disease (ALD) patterns such as fatty liver, alcoholic hepatitis, or cirrhosis can be observed.

Retinol-binding protein (RBP) is a single polypeptide chain protein with a molecular mass of 21kDa (Colantuoni et al., 1983). It is synthesized by the liver, and its known function is to transport retinol from its storage sites in the liver to various target tissues. One single retinol molecule is buried within a highly conserved eight-stranded β-barrel structure of the RBP molecule (Soprano & Blaner, 1994). Holo-RBP is found in a 1:1 molar complex with transthyretin, which prevents excretion of holo-RBP by the kidney (Monaco et al., 1995). The stellate cells in the liver are the major storage site for retinyl esters in the body (Blomhoff & Wake, 1991). In case of delivery of retinol to tissue in the periphery, retinyl esters are hydrolyzed and retinol is bound to the specific binding site of RBP for delivery to target tissues. Those hepatic retinyl ester levels are regulated by class I alcohol dehydrogenase (ADH1) that uses both ethanol and retinol as substrate (Molotkov et al., 2004). This suggests that ethanol may affect vitamin A storage in the liver.

Within the target cells, retinol is oxidized to its active metabolite (all trans-) retinoic acid (Duester, 2000) that binds to the retinoic acid receptor (Giguere et al., 1987), which forms a heterodimer with retinoid X receptor to bind DNA (Zhang et al., 1992). Ethanol, similar to the ADH1 knockout in mice (Molotkov & Duester, 2002), was previously shown to reduce intracellular transformation of retinol to retinoic acid (Mezey and Holt, 1971, Parlesak et al., 2000) and hence to impair differentiation and controlled cell growth by impairing the pleiotropic function of retinoids (Berry, 1997).

Decreased plasma concentrations of both retinol and RBP may result from different kinds of hepatic injury (Smith & Goodman, 1971). Decreased plasma vitamin A as well as RBP concentrations were measured in subjects with alcohol-induced liver cirrhosis (McClain et al., 1979, Smith et al., 1975) or with less advanced alcoholic liver disease (Chapman et al., 1993, Lohle et al., 1982). In contrast, other studies report comparable retinol and RBP concentrations in plasma of alcoholics and controls (Bjorneboe et al., 1987, Lecomte et al., 1994, Zima et al., 2001).

The working hypothesis of the present study was that a decrease in relative saturation of RBP with retinol in patients with ALD may occur and hereby add to the limited availability of retinol in the periphery in addition to the hitherto identified confounders of retinoid metabolism such as increased retinoid degradation by cytochrome P450 and impaired retinol oxidation.

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2. Materials and methods 

2.1. Subjects 

The study was carried out in accordance with the Helsinki Declaration of 1975, as revised in 1983, and was approved by the Ethics Committee of the Robert-Bosch-Hospital, Stuttgart, Germany. Over a period of 4 years, a total of 118 hospitalized patients who gave written informed consent and have consumed more than 60g alcohol/day for more than 1 year were included in the study. All subjects displaying various stages of ALD and not having abstained from alcohol for more than 3 days before admission to the hospital were classified into three groups depending on the severity of liver injury.

Exclusion criteria were age <18 and >70 years, pregnancy, acute pancreatitis, malignancies, cardiac decompensation, bacterial infections, rheumatic diseases, surgery, blood transfusion within the last 3 months, and hepatitis B or C infection. Patients were divided into two groups without cirrhosis and one group with cirrhosis (group ALD3). Patients were classified as having cirrhosis either by liver biopsy or if they met typical clinical criteria—(1) the presence of ascites, esophageal varices, or splenomegaly; and/or (2) the presence of two out of the following three criteria: relative prothrombin time <60%, bilirubin plasma concentration >3.5mg/dl, and serum albumin <2.5g/dl; and (3) the presence of one of the following two criteria: aspartate aminotransferase (AST) >40U/l and γ-glutamyltransferase (γ-GT) >100U/l (Table 1). Those patients who did not meet the criteria of cirrhosis were assigned to group ALD2, if alanine aminotransferase (ALT) in serum was >35U/l and bilirubin was above 1.5mg/dl, or if AST in serum was >40U/l. Additional criteria to meet for patients in group ALD2 were an AST/ALT quotient >1 and a γ-GT activity in serum >55U/l. Group ALD1 comprised patients in whom bilirubin and relative prothrombin time were in the normal range, AST in serum was <40U/l, and ALT in serum was <35U/l. In patients who were probed for liver biopsies for routine analysis, histological diagnosis was used in addition to assign patients with the diagnosis “fatty liver” to group ALD1, those with “(alcoholic) hepatitis” to group ALD2, and those with the classification “cirrhosis” to group ALD3. Due to refusal of patients, risk of complication during sampling, or a reduced coagulation, liver biopsies were obtained from only 30 patients with ALD (ALD1: 7, ALD2: 12, and ALD3: 11). However, in all cases the biopsy assessment confirmed the assignment of patients with fatty liver to group ALD1, those with hepatitis to group ALD2, and those with cirrhosis to group ALD3. Therefore, the probability of a classification not resulting in the histological assignment “fatty liver,” “hepatitis,” and “cirrhosis” to groups ALD1–3, respectively, was less than 0.1% (P<.001; Chi-square test).

Table 1. Clinical, laboratory, and anthropometric parametersa of patients on admission and of healthy controls
VariablesNoncirrhotic ALDCirrhotic ALDHealthy controls
ALD1ALD2ALD3
n (male/female)53 (48/5)29 (26/3)36 (25/11)45 (32/13)
Age (years)49±1.748±2.052±1.847±1.6
BMI (kg/m2), 18–25b24.1±0.624.0±0.825.8±0.924.1±0.5
AST (U/l), 2–19b22±1.372±5.5**57±9.7**12±0.4
ALT (U/l), 5–24b22±1.457±6.2**27±3.616±1.0
AST/ALT1.1±0.071.6±0.14**2.0±0.14**0.8±0.03
γ-GT (U/l), 6–28b103±19591±89**365±69**13±2
Bilirubin (mg/dl), 0.2–1.4b1.1±0.081.5±0.115.8±1.35**0.8±0.05
Relative prothrombin time (%)c, 70–100b93±1.491±2.259±2.9**97±1.3
Albumin (g/dl), 3.5–5.0b4.0±0.164.0±0.143.4±0.15*4.2±0.12

ALD1, ALD2, and ALD3 denote patients with mild, moderately severe, and severe stages of alcohol-induced liver disease (ALD), respectively.

*P<.01; **P<.001 as compared to controls; calculated by analysis of variance and post hoc test of Tukey.

BMI=body mass index; AST=aspartate aminotransferase; ALT=alanine aminotransferase; γ-GT=γ--glutamyltransferase.

aAll data are expressed as mean±S.E.M.

bNormal range.

cPercentage of normal values.

Forty-five subjects who consumed less than 20g alcohol per day and who were evidently healthy served as controls. The controls were matched by age and sex to the patients participating in the study.

2.2. Diet history 

Both cases and controls were nutritionally assessed by a trained nutritionist using a computerized, established method of obtaining a diet history, which has been validated (Landig et al., 1998). The program of this method is based on the German food and nutrient database Bundeslebensmittelschlüssel. This database includes 11,000 food items and recipes. To improve the estimation of their usual portion size for each item, subjects were provided with photographs of small, medium, or large serving sizes of the most frequently consumed foods. The patients were asked in detail about their frequency of alcohol consumption and serving size in terms of medium glasses or bottles of wine, 0.3-l cans or bottles of beer, or shots of hard liquor. For calculation of mean daily alcohol consumption, the following alcohol concentrations (vol/vol) were assumed: beer 4%, wine 11%, and hard liquors 40%.

2.3. Collection of blood samples 

Within 48h after admission to the hospital, venous blood samples for measurement of retinol and RBP were collected with the addition of heparin after an overnight fast. Plasma was separated by centrifugation at 3,000×g, and aliquots were stored at −80°C until determination. Standard parameters of liver function (AST, ALT, γ-GT, bilirubin, albumin, and relative prothrombin time) were measured during routine analysis in the central hospital unit for clinical chemistry.

2.4. Chemical and biochemical methods 

All measurements were carried out in duplicate. The content of retinol in plasma was determined by using the modified high-performance liquid chromatography method of Hess et al. (1991). In brief, ethanol (500μl) was added to the plasma samples (200μl) to precipitate the proteins, and the fat-soluble vitamins were extracted with n-hexane (anti-oxidant: 2,[6]-di-tert-butyl-p-cresol [Sigma–Aldrich, Steinheim, Germany]). The organic solvent was removed and the residue was redissolved in 250μl dioxan/ethanol/acetonitrile (20/20/60: vol/vol/vol). The retinol concentration was determined on a reversed phase column (Nucleosil 120-5 C 18, 250×3mm: CS-Chromatographie Service, Langerwehe, Germany) by using acetonitrile/tetrahydrofuran/methanol/1% ammonium acetate (684/220/68/28: vol/vol/vol/vol) as the mobile phase at a flow rate of 0.7ml/min. All solvents and chemicals were purchased from Serva, Heidelberg, Germany or Merck, Darmstadt, Germany. Detection wavelength for retinol was 325nm. A National Institute of Standards and Technology (Gaithersburg, USA) standard was used to perform calibration. The limit of detection was 0.027μmol/l. The recovery was 106±10% (±S.D.) and the intraday coefficient of variation was 5.3%; the interday coefficient of variation was 12.4%.

The RBP concentrations in plasma were measured in duplicate by an enzyme-linked immunosorbent assay method (DAKO, Glostrup, Denmark) due to the guidelines of the manufacturer. Absorption was measured at 450nm in a microplate reader (Tecan SLT-Labinstruments, Crailsheim, Germany) with 650nm as the reference wavelength. The RBP standard was delivered by Sigma, Taufkirchen, Germany. The intra-assay coefficient of variation was 24% at a concentration of 20ng/ml; the accuracy of the mean was +12%. The relative saturation of RBP with retinol (%) was calculated for each subject by dividing the plasma retinol concentration (μmol/l) by the plasma RBP concentration (μmol/l). For the calculation of molar concentration of RBP, a molecular mass of 21,000g/mol was presumed (Colantuoni et al., 1983).

2.5. Statistical analysis 

All results are given as mean±S.E.M. Analyses of variance (ANOVAs, one way) with the consequent post hoc test of Tukey were applied for the determination of significance levels (Statistica Version 6.0 software, StatSoft, Inc., Tulsa, USA). Value distributions within the single groups were checked for homogeneity of variances (Bartlett's test) to meet the requirements for applicability of ANOVA. Differences were considered as significant if the P value was less than .05. Correlations between the concentrations of plasma retinol, RBP or the retinol/RBP quotient, and clinical parameters were calculated with the nonparametric test of Spearman.

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3. Results 

No significant differences between patients with increasing severity of alcohol-induced liver disease (ALD1–3) and healthy controls were found for age, body weight, and body mass index. As expected due to the classification criteria, the results of tests representing liver function and liver damage (bilirubin, albumin, relative prothrombin time, AST, ALT, γ-GT, and AST/ALT) were above/below normal ranges in all ALD groups (Table 1).

Major differences in calorie intake occurred only when alcohol was integrated in the nutritional balance (Table 2). Without alcohol, energy intake differed only moderately for subjects of group ALD1 due to a higher consumption of carbohydrates and protein. Although slightly lower in ALD patients, the differences in retinol intake were not significant. β-carotene intake was lower in patients of groups ALD1 and ALD3 in comparison to healthy controls (Table 2).

Table 2. Daily intakea of energy, alcohol, fat, protein, carbohydrate, retinol, and β-carotene in groups ALD1–3 and in control subjects
VariablesNoncirrhotic ALDCirrhotic ALDHealthy controls
ALD1ALD2ALD3
Alcohol (g/day)150±19160±20107±119±1
Total energy (kcal/day)4,165±3433,345±2732,816±1552,499±85
Energy without alcohol (kcal/day)3,103±281*2,210±2032,055±1352,437±83
Protein (g/day)116±10*84±879±688±4
Fat (g/day)126±1181±1081±6109±5
Carbohydrate (g/day)360±36*277±27249±18265±12
Retinol (μg/day)1,412±1861,199±166986±1371,413±126
β-carotene (mg/day)3.3±0.3*3.4±0.42.9±0.3*4.6±0.4

ALD1, ALD2, and ALD3 denote patients with mild, moderately severe, and severe stages of alcohol-induced liver disease (ALD), respectively.

*P<.01; as compared with controls.

ALD=alcohol-induced liver disease.

aAll data are expressed as mean±S.E.M.

When comparing plasma concentrations of RBP in subjects and controls, patients of group ALD2 displayed the highest mean value of RBP. Both the RBP concentration in controls and that in the groups ALD1 and ALD3 were significantly lower than that in subjects of group ALD2 (Fig. 1).

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  • Fig. 1. 

    Concentrations of retinol-binding protein (RBP) in plasma of patients with increasing severity of alcohol-induced liver disease (ALD1–3) and healthy controls (C). Groups ALD1, ALD2, and ALD3 consist of patients with mild, moderately severe, and severe stages of alcohol-induced liver disease. Values are given as mean±S.E.M. Different letters denote significant differences. ALD2 versus ALD3: P<.001; all other differences P<.05.

The average plasma concentration of retinol was found to be significantly reduced in alcohol abusers of all ALD groups compared with healthy controls, the decrease being most pronounced in subjects of group ALD3 (Fig. 2). With increasing severity of ALD, the relative saturation of RBP with retinol decreased significantly (Fig. 3) and was significantly lower in the plasma of all patient groups compared to that of the control group.

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  • Fig. 2. 

    Retinol concentrations in plasma of patients with alcohol-induced liver disease (ALD1–3) and healthy controls (C). Groups ALD1, ALD2, and ALD3 consist of patients with mild, moderately severe, and severe stages of alcohol-induced liver disease. Values are given as mean±S.E.M. Different letters denote significant differences. C versus ALD1: P<.001; ALD3 versus C, ALD1, ALD2: P<.001.

  • View full-size image.
  • Fig. 3. 

    Relative saturation of retinol-binding protein (RBP) with retinol in the blood of patients with increasing severity of alcohol-induced liver disease (ALD1–3) and healthy controls (C). Groups ALD1, ALD2 and ALD3 consist of patients with, mild, moderately severe, and severe stages of alcohol-induced liver disease. Values are given as mean ± S.E.M. Different letters denote significant differences. C versus ALD2: P<.01; C versus ALD3: P<.001; ALD1 versus ALD3: P<.01.

Spearman analysis revealed a highly significant negative correlation coefficient (r) between the relative saturation of RBP with retinol and AST (r=−0.36; P<.001), AST/ALT (r=−0.45; P<.001), γ-GT (r=−0.37; P<.001), bilirubin (r=−0.36; P<.001), and the daily consumed amount of alcohol (r=−0.29; P<.001). The relative saturation of RBP with retinol (%) correlated positively with albumin (r=0.48; P<.001).

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4. Discussion 

Among the detrimental effects of ethanol on retinoid metabolism, three different possibilities of interference were demonstrated so far.

First, several subclasses of cytosolic alcohol dehydrogenases (ADHs) were shown to catalyze the oxidation of retinol to retinal (Yang et al., 1994), which is the rate-limiting step in retinoic acid synthesis (Duester, 2000). Ethanol was shown to impair ADH-mediated oxidation of retinol in the purified iso-enzymes (Julia et al., 1986), in rat liver and intestine (Parlesak et al., 2000, Parlesak et al., 2005), in mouse liver (Molotkov & Duester, 2002), and in human liver (Mezey & Holt, 1971).

Second, ethanol induces cytochrome P450 enzymes, which convert retinoic acid into polar metabolites (Leo et al., 1989, Liu et al., 2001), which in turn results in an increased catabolism of retinoids in several organs. In addition, toxicity of the formed polar retinoid metabolites may contribute to loss of hepatocytes (Dan et al., 2005, Liu et al., 2002).

Third, chronic ethanol consumption can mobilize vitamin A from the liver to other organs and peripheral tissues (Leo et al., 1986, Mobarhan et al., 1991).

To the best of our knowledge, the saturation of RBP with retinol, which is an important factor for sufficient retinol supplementation of peripheral cells, has not been measured so far in ALD. The results of the present study point out an additional pathway of impairment in retinol metabolism occurring after chronic alcohol abuse, namely a reduction in the saturation of RBP in the blood. Previously, numerous studies investigated separately the effect of ethanol on the plasma concentrations of retinol and RBP. Sato and Lieber (1982) measured decreased plasma-RBP concentrations and lowered hepatic vitamin A levels in rats after acute doses of alcohol, whereas in the same experiments, plasma retinol concentrations were elevated due to an increased release of hepatic retinol or due to a decreased uptake of retinyl esters by the liver. After chronic alcohol consumption, lower hepatic retinol concentrations, but unchanged plasma concentrations of retinol and RBP, were measured in baboons and rats (Sato & Lieber, 1981). Plasma retinol as well as RBP concentrations were reported to be decreased in patients with alcohol-induced liver cirrhosis (McClain et al., 1979, Smith et al., 1975), which has been attributed to a poor dietary intake of this vitamin in alcoholics with or without cirrhosis (Lieber, 1993, McClain et al., 1979, Smith and Goodman, 1971). In parallel to the study of Bergheim et al. (2003), the present study cannot corroborate the hypothesis of malsupplementation being the crucial factor for hypovitaminosis A in patients with ALD.

In other studies, no differences in the plasma concentrations of retinol and RBP between alcoholics and controls were found (Bjorneboe et al., 1987, Lecomte et al., 1994, Zima et al., 2001). However, in these studies no differentiation of the severity of ALD was performed. As statistically significant changes may occur only in single subgroups of patients with ALD (such as RBP concentrations in patients of group ALD2 in the present study), pooling values from patient groups with different stages of ALD or with only mildly affected liver function may blur significant changes in RBP or retinol concentrations in the blood.

In contrast to Cavanna et al. (1985), who postulated RBP to be an important value for the diagnosis of acute and chronic liver disease, in our study plasma levels of RBP were not generally lower in patients with ALD. The highest RBP concentrations were found in patients of group ALD2, nearly each of them exhibiting signs of active alcohol-induced liver injury, as assessed by increased plasma concentrations of AST. This finding stands in contrast to the classification of RBP as a negative acute phase protein that decreases during an acute phase response (Milland et al., 1990). Smith and Goodman (1971) attribute low plasma RBP concentrations in patients with liver damage to a defective and decreased synthesis of RBP by the liver, which evidently does not hold true in patients of group ALD2. It is noteworthy that each of the liver biopsies obtained from these subjects showed an active alcohol-induced hepatitis. If the liver becomes depleted of retinol stores, as in stages of vitamin A deficiency, apo-RBP is retained in the endoplasmic reticulum and accumulates in hepatocytes because the secretion but not the synthesis of RBP is reduced (Dixon and Goodman, 1987a, Dixon and Goodman, 1987b, Perozzi et al., 1991). In our study, the inverse association between the plasma concentrations of retinol and RBP indicates that chronic alcohol consumption impairs the self-regulating mechanism of retinol transport into peripheral tissue. Even though subjects with alcohol-induced liver disease (ALD1–3) had significantly lower concentrations of retinol in the plasma, there was no recognizable decrease in RBP levels with the severity of ALD. A possible explanation for the finding of the highest RBP concentrations in subjects of ALD2 may be an increased release of accumulated RBP from hepatocytes due to ongoing cell damage during inflammation.

The inconsistent findings of the studies mentioned above reveal that plasma concentrations of retinol and RBP alone are not definitely associated with the severity of ALD. A possible approach to use retinol and RBP as markers for ALD is to use the relative saturation of RBP with retinol. Under normal conditions, nearly equimolar plasma concentrations of retinol and RBP are found in the circulation (Blomhoff et al., 1991). The few known human studies that focused on retinol/RBP ratios in the blood of adults indicate reference values from 62 to 93% (Ingenbleek et al., 1975, Smith et al., 1973a, Smith et al., 1973b). The relative saturation of RBP with retinol closely correlates to the ongoing damage of the liver caused by chronic alcohol abuse, as reflected in both the hepatocyte injury (plasma activities of AST) and overall functionality of the liver organ (plasma concentrations of bilirubin/albumin and relative prothrombin time). The diminishing retinol/RBP ratio implicates an excess of RBP in circulation, which may result in a decreased availability of retinol to the target cells because of the competition between RBP and the cell for retinol. This effect might be aggravated by competition between ethanol and retinol for binding to RBP (as observed for ADH1), but this hypothesis needs future experimental support. However, a decreased RBP saturation already occurs in patients without signs of severe ALD (group ALD1). So we conclude that a decreased saturation of RBP and thus a diminished availability of retinol in the periphery occurs already at early stages of liver damage caused by alcohol abuse.

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Acknowledgments 

This work was supported by a grant (70-1881-Bo 1) to A.P. and C.B. from the “Mildred-Scheel-Stiftung,” Bonn, Germany. The authors thank Drs. Elke-Tatjana Schütz and Jens Diedrich, who supported the study by recruitment of patients and sample collection. The authors also acknowledge support by Ch. Lengger in the measurement of retinol concentrations.

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References 

  1. Bergheim I, Parlesak A, Dierks C, Bode JC, Bode C. Nutritional deficiencies in German middle-class male alcohol consumers: relation to dietary intake and severity of liver disease. Eur J Clin Nutr. 2003;57:431–438
  2. Berry C. Retinoic acid, neoplasia, differentiation and development. Virchows Arch. 1997;430:267–270
  3. Bjorneboe GA, Johnsen J, Bjorneboe A, Morland J, Drevon CA. Effect of heavy alcohol consumption on serum concentrations of fat-soluble vitamins and selenium. Alcohol Alcohol Suppl. 1987;1:533–537
  4. Blomhoff R, Green MH, Green JB, Berg T, Norum KR. Vitamin A metabolism: new perspectives on absorption, transport and storage. Physiol Rev. 1991;71:951–990
  5. Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J. 1991;5:271–277
  6. Cavanna A, Giovine G, Tappero R, Torchio M, Avagnina P, Molino G. Diagnostic value of prealbumin and retinol-binding protein in acute and chronic liver disease. Ric Clin Lab. 1985;15:71–77
  7. Chapman KM, Prabhudesai M, Erdman JW. Vitamin A status of alcoholics upon admission and after two weeks of hospitalization. J Am Coll Nutr. 1993;12:77–83
  8. Colantuoni V, Romano V, Bensi G, Santoro C, Costanzo F, Raugei G, et al. Cloning and sequencing of a full length cDNA coding for human retinol-binding protein. Nucleic Acids Res. 1983;11:7769–7776
  9. Dan Z, Popov Y, Patsenker E, Preimel D, Liu C, Wang XD, et al. Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J. 2005;19:845–847
  10. Day CP. Alcoholic liver disease: dose and threshold—new thoughts on an old topic. Gut. 1997;41:857–858
  11. Dixon JL, Goodman DS. Effects of nutritional and hormonal factors on the metabolism of retinol-binding protein by primary cultures of rat hepatocytes. J Cell Physiol. 1987;130:6–13
  12. Dixon JL, Goodman DS. Studies on the metabolism of retinol-binding protein by primary hepatocytes from retinol-deficient rats. J Cell Physiol. 1987;130:14–20
  13. Duester G. Families of retinoid dehydrogenases regulating vitamin A function. Production of visual pigment and retinoic acid. Eur J Biochem. 2000;267:4315–4324
  14. Feuerlein W. Zur Mortalität von Suchtkranken. In:  Mann K,  Buchkremer G editor. Sucht—Grundlagen, Diagnose, Therapie. Stuttgart, Jena, New York: Fischer; 1996;p. 213–230
  15. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature. 1987;330:624–629
  16. Hess D, Keller HE, Oberli B, Bonfanti R, Schuep W. Simultaneous determination of retinol, tocopherols, carotenes and lycopene in plasma by means of high-performance liquid chromatography on reversed phase. Int J Vitam Nutr Res. 1991;61:232–238
  17. Ingenbleek Y, Van Den Schrieck HG, De Nayer P, De Visscher M. The role of retinol-binding protein in protein malnutrition. Metabolism. 1975;24:633–641
  18. Julia P, Farres J, Pares X. Ocular alcohol dehydrogenase in the rat: regional distribution and kinetics of the ADH-1 isoenzyme with retinol and retinal. Exp Eye Res. 1986;42:305–314
  19. Landig J, Erhardt JG, Bode JC, Bode C. Validation and comparison of two computerized methods of obtaining a diet history. Clin Nutr. 1998;17:113–117
  20. Lecomte E, Grolier P, Herbeth B, Pirollet P, Musse N, Paille F, et al. The relation of alcohol consumption to serum carotenoid and retinol levels. Effects of withdrawal. Int J Vitam Nutr Res. 1994;64:170–175
  21. Leo MA, Kim C, Lieber CS. Increased vitamin A in esophagus and other extrahepatic tissues after chronic ethanol consumption in the rat. Alcohol Clin Exp Res. 1986;10:487–492
  22. Leo MA, Lasker JM, Raucy JL, Kim CI, Black M, Lieber CS. Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Arch Biochem Biophys. 1989;1269:305–312
  23. Lieber CS. Herman Award Lecture, 1993: a personal perspective on alcohol, nutrition and the liver. Am J Clin Nutr. 1993;58:430–442
  24. Lieber CS. Alcohol and the liver: 1994 update. Gastroenterology. 1994;106:1085–1105
  25. Liu C, Chung J, Seitz HK, Russell RM, Wang XD. Chlormethiazole treatment prevents reduced hepatic vitamin A levels in ethanol-fed rats. Alcohol Clin Exp Res. 2002;26:1703–1709
  26. Liu C, Russell RM, Seitz HK, Wang XD. Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P450E1. Gastroenterology. 2001;120:179–189
  27. Lohle E, Schölmerich J, Vuilleumier JP, Köttgen E. Vitamin A concentration in plasma and ability to hear in patients with chronic alcoholic liver disease. HNO. 1982;30:375–380
  28. McClain CJ, Van Thiel DH, Parker S, Badzin LK, Gilbert H. Alteration in zinc, vitamin A and retinol-binding protein in chronic alcoholics: a possible mechanism for night blindness and hypogonadism. Alcohol Clin Exp Res. 1979;3:135–140
  29. Mezey E, Holt PR. The inhibitory effect of ethanol on retinol oxidation by human liver and cattle retina. Exp Mol Pathol. 1971;15:148–156
  30. Milland J, Tsykin A, Thomas T, Aldred AR, Cole T, Schreiber G. Gene expression in regenerating and acute-phase rat liver. Am J Physiol. 1990;259:G340–G347
  31. Mobarhan S, Seitz HK, Russell RM, Mehta R, Hupert J, Friedman H, et al. Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. J Nutr. 1991;121:510–517
  32. Molotkov A, Duester G. Retinol/ethanol drug interaction during acute alcohol intoxication in mice involves inhibition of retinol metabolism to retinoic acid by alcohol dehydrogenase. J Biol Chem. 2002;277:22553–22557
  33. Molotkov A, Ghyselinck NB, Chambon P, Duester G. Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation. Biochem J. 2004;383:295–302
  34. Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995;268:1039–1041
  35. Parlesak A, Ellendt K, Lindros KO, Bode C. Acute but not chronic ethanol exposure impairs retinol oxidation in the small and large intestine of the rat. Eur J Nutr. 2005;44:157–162
  36. Parlesak A, Menzl I, Feuchter A, Bode JC, Bode C. Inhibition of retinol oxidation by ethanol in the rat liver and colon. Gut. 2000;47:825–831
  37. Perozzi G, Mengheri E, Colantuoni V, Gaetani S. Vitamin A intake and in vivo expression of the genes involved in retinol transport. Eur J Biochem. 1991;196:211–217
  38. Sato M, Lieber CS. Hepatic vitamin A depletion after chronic ethanol consumption in baboons and rats. J Nutr. 1981;111:2015–2023
  39. Sato M, Lieber CS. Changes in vitamin A status after acute ethanol administration in the rat. J Nutr. 1982;112:1188–1196
  40. Smith FR, Goodman DS. The effects of diseases of liver, thyroid, and kidney on the transport of vitamin A in human plasma. J Clin Invest. 1971;50:2426–2436
  41. Smith FR, Goodman DS, Arroyave G, Viteri F. Serum vitamin A, retinol-binding protein, and prealbumin concentrations in protein-calorie malnutrition. II. Treatment including supplemental vitamin A. Am J Clin Nutr. 1973;26:982–987
  42. Smith FR, Goodman DS, Zaklama MS, Gabr MK, el-Maraghy S, Patwardhan VN. Serum vitamin A, retinol-binding protein, and prealbumin concentrations in protein-calorie malnutrition. I. A functional defect in hepatic retinol release. Am J Clin Nutr. 1973;26:973–981
  43. Smith JC, Brown ED, White SC, Finkelson JD. Plasma vitamin A and zinc concentration in patients with alcoholic cirrhosis. Lancet. 1975;1:1251–1252
  44. Soprano DR, Blaner WS. Plasma retinol-binding protein. In:  Sporn MB,  Roberts AB,  Goodman DS editor. The Retinoids, Biology, Chemistry and Medicine. New York: Raven Press; 1994;p. 257–282
  45. Yang ZN, Davis GJ, Hurley TD, Stone CL, Li TK, Bosron WF. Catalytic efficiency of human alcohol dehydrogenases for retinol oxidation and retinal reduction. Alcohol Clin Exp Res. 1994;18:587–591
  46. Zhang XK, Hoffmann B, Tran PB, Graupner G, Pfahl M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature. 1992;355:441–446
  47. Zima T, Fialova L, Mestek O, Janebova M, Crkovska J, Malbohan I, et al. Oxidative stress, metabolism of ethanol and alcohol-related diseases. J Biomed Sci. 2001;8:59–70

PII: S0741-8329(06)00046-2

doi:10.1016/j.alcohol.2006.03.007

Alcohol
Volume 38, Issue 1 , Pages 37-43, January 2006

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