bluuebunny/crossref_metadata_2025 huggingface dataset:
Conference Summary: Consensus Conference on Alcohol Dependence and the Role of Pharmacotherapy in its Treatment
Authors: Chick Jonathan , Erickson Carlton K.
Published: April 2006

Alcoholism, a major public health problem throughout the world, causes enormous damage to health and quality of life and undermines the well‐being of families and society. It is associated with liver disease, cancer, cardiovascular problems, accidental deaths, suicides, and homicides. Because of the internationally recognized severity of this disease, this consensus conference was convened to bring together leading international experts to share ideas with regard to current research in the areas of alcohol dependency and treatment, and to discuss the future directions for the pharmacotherapy of alcoholism. The work presented at this conference points to a substantial evolution in the ability of researchers to understand the mechanism by which alcohol acts on the brain and reinforces the concept that alcoholism is a disease of brain chemistry, with a hereditary predisposition that is triggered by psychological and/or environmental factors that are thus far unidentified. The consensus statements proposed by the participants at the close of the conference highlight the definition, etiology, and prevention of alcoholism, as well as current and potential treatments and recommendations that can be used to guide future pharmacologic research.
8‐Bromo‐cAMP Mimics β‐Adrenergic Sensitization of GABA Responses to Ethanol in Cerebellar Purkinje Neurons in vivo
Authors: Freund Ronald K. , Palmer Michael R.
Published: April 2006

Previous studies in our laboratory indicated that electrophysiological responses of cerebellar Purkinje neurons to GABA were not routinely potentiated by ethanol (EtOH), and the potentiation was not large when it occurred. In the presence of β‐adrenergic agonists, such as isoproterenol, however, GABA inhibitions became sensitive to potentiation by EtOH in nearly every Purkinje neuron tested. β‐Adrenergic receptor activation alone also modulates (potentiates) GABA responses on Purkinje neurons, and this has been reported to be mediated by a cAMP second messenger system. Herein, we report that the membrane‐permeable cAMP analog, 8‐bromoadenosine‐3′,5′‐cyclic monophosphate (8‐Br‐cAMP), but not the membrane‐impermeable cAMP, can also modulate GABA responses and that EtOH potentiates this facilitatory action of 8‐Br‐cAMP. These effects are not likely caused by adenosine receptor mechanisms, because this 8‐bromoadenosine mediated modulation and sensitization was observed in the presence of systemic theophylline. These data suggest that the β‐adrenergic modulation and sensitization to EtOH of cerebellar Purkinje neuron GABA responses occur via a cAMP second messenger mechanism.
Ethanol Modulates Metastatic Potential of B16BL6 Melanoma and Host Responses
Authors: Blank Sally E. , Meadows Gary G.
Published: April 2006

The experimental metastatic potential (lung‐colonizing ability) of B16BL6 melanoma cells was examined in C57BL/6 mice after exposure to ethanol in vitro and in vivo. In vitro, tumor cells were cultured with ethanol (0.3% v/v), or medium alone, for three passages at 5‐day intervals. In vivo, B16BL6 melanoma was exposed to ethanol by administering ethanol (10% or 20% w/v) to mice following subcutaneous inoculation of tumor cells into the dorsal hip. All tumor cells were subsequently inoculated intravenously into the lateral tail vein of water‐drinking mice to assess changes in metastatic phenotype. Tumor cells cocultured in vivo with ethanol produced significantly higher numbers of superficial lung colonies, compared with tumor cells cultured in control medium. Experimental metastasis of tumor cells obtained from 20% w/v ethanol‐consuming mice was also significantly increased, compared with cells obtained from water‐drinking mice. Metastasis of B16BL6 melanoma cells previously obtained from mice consuming 10% w/v ethanol did not differ from controls. In other experiments, water‐drinking and ethanol‐consuming (2.5%, 10%, and 20% w/v) mice were inoculated subcutaneously into the dorsal hip with B16BL6 melanoma cells, and monitored for tumor growth rate and survival time. In these experiments, survival times were significantly shorter in mice consuming 20% ethanol, compared with all other groups. Subcutaneous tumor growth rate was unaffected by ethanol consumption. Lung metastasis resulting from subcutaneous tumor implantation of B16BL6 melanoma was respectively inhibited, or absent, in 10% and 20% ethanol‐consuming groups. Thus, tumor growth rate and incidence of lung metastases were not apparent determinants of decreased survival in 20% ethanol‐consuming mice. The results of this study indicate that the experimental metastatic potential of B16BL6 melanoma is increased during exposure to ethanol; however, metastasis from subcutaneous tumor‐bearing mice is suppressed. This latter finding is consistent with previous results in which spontaneous metastasis was also suppressed after inoculation of the tumor into the pinna of the ear. Although ethanol increases the ability of B16BL6 melanoma to colonize the lung after intravenous inoculation, this effect is abated in the presence of host factors in ethanol‐consuming mice.
Initiation of Ethanol Self‐Administration by the Sucrose‐Substitution Method with HAS and LAS Rats
Authors: Files Forrest J. , Samson Herman H. , Brice Gary T. , Deitrich Richard A. , Draski Laura J.
Published: April 2006

This study was performed to examine ethanol self‐administration in rats bred for different sensitivities to the sedative effects of alcohol [the Colorado High Alcohol Sensitive (HAS) and Low Alcohol Sensitive (LAS) rats]. Four rats from each replicate line of the HAS and LAS rats (n= 16) were obtained from the University of Colorado, and initiation to self‐administer ethanol by the sucrose‐substitution procedure was attempted. Before the initiation procedure was conducted, home‐cage ethanol intake and preference ratio did not differ between LAS and HAS rats. During the initiation procedure, the LAS rats came to self‐administer 10% ethanol (v/v) at similar levels as outbred Wistar rats initiated with the same procedure (˜0.4 g/kg/ session). The HAS rats, however, failed to initiate (˜0.08 g/kg/session after completing the sucrose‐substitution procedure) and lever pressing was reduced even more in the HAS rats when the ethanol concentration presented was >10% (v/v). Three of the eight HAS rats stopped lever pressing completely when the ethanol concentration was raised to 15%. After initiation, home‐cage preference ratio differed significantly between the LAS and HAS rats (LAS > HAS, p < 0.03). That the LAS rats did not consume greater amounts of ethanol compared with outbred Long‐Evans or Wistar rats is contrary to our hypothesis, based on recent human data suggesting that a lower sensitivity to ethanol could result in increased alcohol intake. The finding that the HAS rats could not be initiated, while selectively bred ethanol nonpreferring rats can, is also contrary to our hypothesis. Further studies related to ethanol self‐administration with the HAS line could provide important information related to the genetics of alcohol nonacceptance.
Effects of Taste Aversion Training on the Acquisition of Alcohol Drinking in Adolescent P and HAD Rat Lines
Authors: McKinzie D. L. , Eha R. , Murphy J. M. , McBride W. J. , Lumeng L , Li T.‐K.
Published: April 2006

Early alcohol drinking has been hypothesized to cause alcohol‐related problems in adulthood. In addition, a potential role for genetic factors exist in the etiology of some types of alcoholism. The objective of the present study was to determine if taste aversion training to ethanol during adolescence in previously ethanol‐naive, alcohol‐preferring P and high‐alcohol drinking HAD‐1 lines of rats would retard or prevent the onset of high alcohol drinking. Taste aversion training began at 30 days of age. Male and female rat pups were fluid‐deprived for 24 hr before 30 min access to a 10% (v/v) ethanol solution, followed by an intraperitoneal injection of either saline or 0.15 M LiCl (10 ml/kg). A total of five training sessions were administered every other day with unrestricted access to water on intervening training days. Twenty‐four hours after the last training trial, rats were given continuous free‐choice between water and 10% ethanol for 4 weeks with food available ad libitum. There were no obvious gender or line differences to the effects of taste aversion training. All LiCl‐treated subjects avoided the usually preferred ethanol solution for the entire 4‐week test period, whereas saline‐treated rats steadily increased their alcohol intake to over 6.0 g/kg/day by week 4. Rats in the saline and LiCl‐treated groups gained weight at comparable rates, and the groups did not differ in total fluid intake. The findings demonstrate that early environmental intervention can prevent the onset of high alcohol drinking in the selectively bred alcohol‐preferring P and high‐alcohol drinking HAD‐1 lines of rats.
DRD2 Haplotypes Containing the TaqI A1 Allele: Implications for Alcoholism Research
Authors: Kidd Kenneth K. , Pakstis Andrew J. , Castiglione Carmela M. , Kidd Judith R. , Speed William C. , Goldman David , Knowler William C. , Lu Ru‐Band , Bonne‐Tamir Batsheva
Published: April 2006

In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the TaqI “A” site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third TaqI restriction fragment‐length polymorphism at DRD2, the TaqI “D” site, has been converted to polymerase chain reaction‐based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the TaqI “B” and “A” sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1‐containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.
Excretion of β‐Carbolines Harman and Norharman in 24‐Hour Urine of Chronic Alcoholics During Withdrawal and Controlled Abstinence
Authors: Wodarz Norbert , Wiesbeck Gerhard Adam , Rommelspacher Hans , Riederer Peter , Böning Jobst
Published: April 2006

Animal experiments suggest that endogenous substances that could result from the interaction between neurotransmitters (dopamine and indoleamines) and ethanol and its metabolite acetaldehyde might be involved in the pathogenesis and maintenance of alcohol dependence. Therefore, aromatic β‐carbolines (norharman and harman) were investigated repeatedly in 24‐hr urine of 13 male severe alcoholics without any psychiatric comorbidity during a controlled inpatient abstention program of up to 8 weeks. Harman excretion was ˜2‐fold above levels in control subjects, with a steady decline after 3 weeks of abstinence and lower levels in patients with a longer duration of alcohol dependence. Severity of withdrawal symptoms and actual feelings of anxiety/depression were negatively associated with urinary harman excretion. Positive associations could be established with daily ethanol consumption the month before admission and the score on the scale “reward dependence” according to Cloninger's Tridimensional Personality Questionnaire. Moreover, patients without alcohol‐dependent first‐degree relatives and higher “reward dependence” exhibited an increased excretion of harman. Therefore, harman levels might characterize a distinct subgroup of alcoholic patients, who in part resemble the so‐called type I alcoholics of Cloninger. However, this awaits further study in a larger number of individuals. In contrast, norharman excretion was elevated up to 6‐fold, compared with nonalcoholics over 6 to 8 weeks of controlled abstention. No correlations to demographic or clinical variables could be observed. Therefore, increased norharman levels might be proposed as a “residual marker” or a trait variable. Whether the observed changes are specific markers of at least certain aspects of alcoholism or dependence remain to be elucidated.
Dose‐Response Studies with Thyrotropin‐Releasing Hormone: Evidence for Differential Pituitary Responses in Men with Major Depression, Alcoholism, or No Psychopathology
Authors: Garbutt James C. , Mayo James P. , Little Karley Y. , Gillette Gregory M. , Mason George A. , Dew Bess , Prange Arthur J.
Published: April 2006

A reduced thyrotropin (TSH) response to thyrotropin‐releasing hormone (TRH) has been reported in both alcoholic and depressed men. To discern whether the pathophysiological basis of a reduced TSH response is similar in these two disorders, the present study compares the dose‐response patterns of TSH and prolactin (PRL) to TRH in depressed, alcoholic, and control men. Four doses of TRH (25, 100, 500, and 800 μg) were given at several day intervals to 6 men with major depression, 8 men with alcohol dependence, and 7 control men. Examination of the pattern of TRH‐induced TSH and PRL response revealed differences for each paired group comparison: depressed versus control, depressed versus alcoholic, and alcoholic versus control. Compared with controls, depressed men had low TSH and low PRL responses to TRH, whereas alcoholic men had low TSH responses and normal PRL responses. Levels of neither thyroid hormones, cortisol, or sex steroids, nor age or body size, explained these differences. These findings suggest that the pathophysiological basis of a reduced TSH response to TRH is different in alcoholism, compared with depression.
Naltrexone Increases the Latency to Drink Alcohol in Social Drinkers
Authors: Davidson Dena , Swift Robert , Fitz Eric
Published: April 2006

We investigated the effects of naltrexone (NTX) on alcohol drinking, urge to drink alcohol, and alcohol‐induced sensations and mood states in social drinkers consuming alcohol ad libitum in a cocktail bar. Sixteen college‐age men and women participated in a double‐blind, placebo‐controlled, within‐subjects, cross‐over study. Subjects were tested during each of three drug conditions: NTX, 50 mg/day, po; inactive placebo; and no drug. Each treatment condition lasted 8 to 11 days. Small groups of subjects consumed alcohol ad libitum during three 2‐hr evening drinking sessions, separated by ˜2 weeks. NTX treatment significantly increased the latency (time in seconds) to first sip the first (p < 0.05) and second alcoholic beverages consumed (p < 0.01). Moreover, the mean blood alcohol concentration at the end of the session was significantly lower when subjects were treated with NTX (p < 0.05). No differences were found on self‐report urge to drink alcohol. Subjects reported more fatigue and tension on the Profile of Mood States (p < 0.05), before drinking, and increases in nausea on the Alcohol Sensation Scale (p < 0.05) when treated with NTX. The increase in the latency to sip the first and second alcoholic beverages may reflect the capacity of NTX to block urge for alcohol elicited from external cues (before consuming alcohol), as well as urge for alcohol after priming from ingested alcohol. Thus, the effectiveness of NTX for reducing drinking behaviors of alcoholics may be partially caused by anticraving properties of NTX.
Executive Cognitive Functioning Predicts Reactive Aggression in Boys at High Risk for Substance Abuse: A Prospective Study
Authors: Giancola Peter R. , Moss Howard B. , Martin Christopher S. , Kirisci Levent , Tarter Ralph E.
Published: April 2006

This study assessed the ability of executive cognitive functioning (ECF) to predict reactive aggression in boys at high and low risk for substance abuse using a 2‐year prospective design. ECF is defined as the self‐regulation of goal‐directed behavior. Reactive aggression involves impulsive hostile reactions committed with little forethought. ECF was measured using five neuropsychological tests in 198 10‐ to 12‐year‐old boys with (SA+) and without (SA‐) a paternal history of substance abuse/dependence. Reactive aggression was measured, 2 years later, using a composite index of items derived from two self‐report measures. It was hypothesized that ECF would predict reactive aggression, and that this relation would be stronger for the SA+ compared with the SA‐ boys. SA+ subjects demonstrated lower ECF scores and higher reactive aggression scores, compared with SA‐ controls. ECF predicted reactive aggression in the SA+ group (β= 0.37, p= 0.001), but not in the SA‐ group (β= 0.09, p= NS). This suggests that compromised ECF may be a risk factor for reactive aggression in SA+ youth. The hypothesis that the relation between ECF and reactive aggression is a manifestation of a mild dysfunction of the prefrontal cortex is discussed.
Platelet Adenylyl Cyclase Activity in Alcoholics and Subtypes of Alcoholics
Authors: Parsian A. , Todd R. D. , Cloninger C. R. , Hoffman P. L. , Ovchinnikova L. , Ikeda H. , Tabakoff B.
Published: April 2006

Adenylyl cyclase (AC) activity was measured in membrane preparations of platelets from control and alcoholic subjects. The sample consisted of 51 alcoholics who were categorized as type I or type II using the criteria of Gilligan et al. (Genet. Epidemiol. 4:395–414, 1987) and 54 normal controls. Alcoholic males exhibited significantly lower values than controls in basal and fluoride‐stimulated platelet AC activity. When male alcoholics were segregated into type I and type II categories, the platelet AC activity did not differ between subtypes, and both subtypes had AC activity that was below control values. Western blot analysis of the quantity of Gsα and Giα proteins in a subset of male controls and alcoholic subjects demonstrated no significant relationship between quantity of G proteins and AC activity. The results confirm lower platelet AC activity in male alcoholics, compared with controls. Given the lack of quantitative relations between Gsα and Giα proteins and AC activity, the results support the contention that individual differences in platelet AC activity in the alcoholic subjects may reflect quantitative or qualitative differences in the AC catalytic units.
Thinning of the Corpus Callosum in Older Alcoholic Men: A Magnetic Resonance Imaging Study
Authors: Pfefferbaum Adolf , Lim Kelvin O. , Desmond John E. , Sullivan Edith V.
Published: April 2006

A brain image averaging technique was applied to three‐dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel‐by‐pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age‐matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional‐deficient condition, Marchiafava‐Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic‐related subsyndromes, such as Marchiafava‐Bignami disease.
Correlates of Past‐Year Status Among Treated and Untreated Persons with Former Alcohol Dependence: United States, 1992
Authors: Dawson Deborah A.
Published: April 2006

Past‐year status was investigated in a sample of 4,585 adults with prior DSM‐IV alcohol dependence. Those who had and had not received treatment for alcohol problems were compared in terms of past‐year status and its correlates, to see if the experience of treatment samples would be reflective of the course of alcoholism in the general population. In the past year, 27.8% of the total sample met the criteria for alcohol abuse or dependence, 22.3% were abstinent, and 49.9% were drinkers who did not satisfy the criteria for either abuse or dependence. Persons who had been treated for alcohol problems were about twice as likely to be abstainers as those who had not been treated (38.8% vs. 16.4%), but only about half as likely to fall into the past‐year category of drinking without abuse or dependence (28.0% vs. 57.8%). These differentials were of constant magnitude, regardless of the interval since the onset of dependence. For the sample as a whole, persons who had received treatment were slightly more likely than their untreated counterparts to have had alcohol abuse or dependence in the past year (33.2% vs. 25.8%), and this differential increased with the interval since the onset of dependence. The odds of both past‐year abstinence and drinking without abuse or dependence were decreased by male gender, Black race, rapidity of the onset of dependence and ethanol intake per drinking day, and were increased by ever having been married and by later ages at onset of dependence. The odds of drinking without abuse or dependence relative to abstinence were increased by college attendance and reduced by the number of dependence symptoms, and having been a daily drinker was associated with increased odds of past‐year abstinence. Treatment history modified the associations between past‐year status and race, marital and educational status, number of past alcohol problems, and rapidity of onset of dependence and age at onset. These results suggest that treatment studies may not be generalizable to alcoholics who do not seek treatment.
Biological Responses to Administered Interferon in Alcoholics
Authors: Ono K. , Sata M. , Murashima S. , Fukuizumi K. , Suzuki H. , Tanikawa K.
Published: April 2006

To elucidate the influence of chronic alcohol intake on interferon (IFN) therapy in patients with various diseases, 3 million units of natural IFN (nHulFN‐αLy) was administered once to alcoholics, nonalcoholic chronic hepatitis C (CH‐C) patients, and healthy subjects. The serial changes of serum activity of 2′4′ oligoadenylate synthetase, Serum levels of β2‐microglobulin, C‐reactive protein (CRP), and body temperature were monitored. The increase in the activity of 2′‐5′ oligoadenylate synthetase, the response of serum‐reactive protein, and body temperature after IFN administration were significantly lower in the alcoholics than those in CH‐C group, and healthy subjects (control group). The serum β2‐microglobulin level was already higher in the alcoholics before IFN administration than those of the control group and the CH‐C group. These findings suggest that physiological responses to exogenous IFN in alcoholics are generally decreased. Hence, for the maximum effect of IFN therapy, it is important for patients to abstain from alcohol intake and for doctors to carefully consider the timing of initiation.
Distribution of Peripheral Blood Lymphoid Subsets in Alcoholic Liver Cirrhosis: Influence of Ethanol Intake
Authors: Laso Francisco Javier , Madruga José Ignacio , López Antonio , Ciudad Juana , Alvarez‐Mon Melchor , Miguel Jesus San , Orfao Alberto
Published: April 2006

The aim of the present study was to investigate the effect of chronic ethanol (EtOH) consumption on the immune system in patients with alcoholic liver cirrhosis (ALC), as analyzed by the distribution of peripheral blood (PB‐) T, B, and NK lymphoid subsets using multiple stainings with monoclonal antibodies and flow cytometry. For that purpose, we have analyzed a group of patients with ALC and active EtOH intake (ALCET group) which were re‐evaluated 3 months after alcohol withdrawal. As controls, both ALC patients with at least 1 year of alcohol withdrawal (ALCAW group) and healthy subjects were used. Regarding the alcohol intake period, the most relevant findings were a significant activation of the PB T‐cell compartment, and specifically of the TCR alpha beta+ subset, as reflected by an increased expression of both the HLA DR and CD11c antigens as well as a significant increase of both the PB NK cells (CD3‐/CD56+) and the cytotoxic T cells coexpressing the CD3 and CD56 molecules. In addition, a decrease of both the numbers of total B cells and their CD5+/CD19+ subset were observed. After a relatively short withdrawal period (3 months), the abnormalities of T, P, and NK cells disappeared. These findings suggest the existence of a close relationship between EtOH consumption and the abnormalities of the immune system observed during active alcoholism. Nevertheless, ALCAW individuals displayed marked alterations on the immunophenotypic profile, as reflected by a significantly decreased number of total T cells, due to reduced levels of the CD3+/TCR alpha beta+, CD4+, CD8+, and CD4+/CD45RA+ T‐cell subsets. In addition, a significantly decreased number of total PB B cells was observed in this group of patients. Our results show that in patients suffering from ALC, the abnormalities of the immune system due to a direct effect of EtOH intake (or its metabolites) should be distinguished from the immunological alterations related to the liver disease itself.
Ethnic Differences in Gastric α‐Alcohol Dehydrogenase Activity and Ethanol First‐Pass Metabolism
Authors: Dohmen Kazufumi , Baraona Enrique , Ishibashi Hiromi , Pozzato Gabriele , Moretti Michele , Matsunaga Chika , Fujimoto Kazuma , Lieber Charles S.
Published: April 2006

We assessed whether the low α‐alcohol dehydrogenase (ADH) activity in Japanese (compared with Caucasians) affects the first‐pass metabolism of ethanol. ADH isozyme activities were determined in endoscopic biopsies of the gastric corpus from 24 Japanese and 41 Caucasian men by starch gel electrophoresis and by comparing the reduction of m‐nitrobenzaldehyde (a preferred substrate of α‐ADH) with that of acetaldehyde (a preferred substrate of γ‐ADH) and the glutathione‐dependent formaldehyde oxidation (a specific reaction of χ‐ADH). Alcohol pharmacokinetics was compared in 10 Japanese and 10 Caucasians after administration of ethanol (300 mg/kg of body weight) intravenously or orally, using 5 and 40% oral solutions. Japanese exhibited lower α‐ADH activity than Caucasians, with no difference in the other gastric isozymes. With 5% ethanol, first‐pass metabolism was strikingly lower in Japanese than in Caucasions. Blood alcohol levels were similar because of the high elimination rate in Japanese due to the hepatic β2‐ADH variant. With 40% ethanol, the first‐pass metabolism increased in both groups to comparable levels, suggesting an additional contribution by χ‐ADH at high ethanol concentrations. These results indicate that α‐ADH activity contributes significantly to gastric ethanol oxidation and its lower activity in Japanese is associated with lesser first‐pass metabolism.
Effects of Bezafibrate on Ethanol Oxidation in Rats
Authors: Tsukamoto Shojiro , Kanegae Takashi , Isobe Eiji , Hirose Makoto , Shimamura Masao , Nagoya Tadaaki
Published: April 2006

Bezafibrate is used to lower serum lipid levels in humans. Fibrate derivatives induce an enzyme participating in the β‐oxidation by peroxisomes. We gave ethanol (2 g/kg) orally to bezafibrate‐treated (300 mg/kg) male rats of the Wistar strain. Blood ethanol levels were remarkably lower and ethanol elimination stood at 432.6 mg/kg/hr (control, 336.6 mg/kg/hr) in the bezafibrate group (p < 0.01). Blood acetate levels were conversely higher in the bezafibrate group. The fatly acid β‐oxidation activity of liver peroxisome in bezafibratetreated, clofibrate‐treated, or γ‐linolenic acid‐treated rats for 4 days was assayed. The activity was 5.8‐fold higher in rats given bezafibrate, 5.4‐fold in the clofibrate (p < 0.01), and 2.0‐fold in the γ‐linolenic acid (p < 0.05). Alcohol dehydrogenase and aldehyde dehydro‐genase activity of cytosol in the liver was not induced by the hypolipidemic drugs, but aldehyde dehydrogenase activity in the liver homogenate was induced. From foregoing results, bezafibrate induced in the organism p‐oxidation by peroxisomes and increased H2O2 production, which led to augmented ethanol metabolism by catalase.
Long‐Term Effects of Chronic Ethanol on Muscarinic Receptor Binding in Rat Brain
Authors: Rothberg Brad S. , Hunter Bruce E. , Walker Don W. , Anderson Jonathon F. , Anderson Kevin J.
Published: April 2006

Effects of chronic ethanol treatment (CET) on muscarinic acetylcholine receptor (mAChR) binding properties were investigated via quantitative autoradiography in rats maintained on an ethanol‐containing liquid diet for 28 weeks and withdrawn from ethanol for 8 weeks before harvesting of tissues. Controls received an identical diet in which sucrose was substituted isocalorically for ethanol. Maximal binding of the radiolabeled mAChR antagonist quinuclidinyl benzilate ([3H]QNB) was not reduced in hippocampal area CA1, dentate gyrus, neocortex, striatum, or thalamus, suggesting that CET results in no significant mAChR loss in these regions. Binding affinities of the cholinergic agonist carbachol to mAChRs were unaffected by CET in each of these regions, as determined by competitive displacement of [3H]QNB labeling. These results suggest that CET‐induced functional deficits in brain cholinergic responses are not due to direct effects of CET on mAChR binding properties.
The Role of Nitric Oxide in Ethanol‐Induced Gastrointestinal Dysfunction
Authors: Keshavarzian Ali , Jacyno Mark , Urban Glenn , Winship Daniel , Fields Jeremy Z.
Published: April 2006

We recently showed that acute ethanol inhibits contractility of the lower esophageal sphincter (LES) and the lower esophageal body (LEB) both in vivo and in vitro. To evaluate the mechanism of this inhibitory effect of ethanol, we investigated the role of nitric oxide (NO) on contractility of isolated LES and LEB circular muscle strips using inhibitors of NO synthase (NOS), NG‐itro‐l‐arginine methyl ester and NG‐nitro‐l‐arginine. Ethanol significantly decreased LES basal tone. This effect was not mediated by NO, because inhibition was not prevented by inhibitors of NOS. Electrical field stimulation caused an On‐response relaxation from LES strips, and an Off‐response contraction from both LES and LEB strips. Inhibitors of NOS prevented the On‐response relaxation of LES, but had no significant effect on LES Off‐response contraction. Ethanol potentiated the On‐response relaxation of the LES Off‐response contraction. Ethanol potentiated the On‐response relaxation of LES, but had no significant effect on Off‐response contraction. Ethanol's potentiating effect of the On‐response relaxation is NO‐mediated, because it was abolished by NOS inhibitors. Ethanol also inhibited carbachol‐induced LES contractility. This inhibitory effect was NO‐mediated, because NOS inhibitors abolished it. Ethanol inhibited both the Off‐response contraction and carbachol‐induced contraction of LEB strips. These effects were not NO‐mediated, because they were not affected by NOS inhibitor. These data suggest that NO is not a mediator for the inhibitory effect of ethanol on LEB contractility, and that NO seems to be a mediator of ethanol inhibition of some aspects of LES motor functions.
Human Hepatocyte Growth Factor in Alcoholic Liver Disease: A Comparison with Change in α‐Fetoprotein
Authors: Mendenhall Charles L. , Roos Filip , Moritz Thomas E. , Roselle Gary A. , Chedid Antonio , Grossman Charles J. , Rouster Susan D. , Bennett Gregory L. , Lake John R. ,   The Department of Veterans Affairs Cooperative Study Group 275
Published: April 2006

To evaluate the hepatic regenerative response in patients with alcoholic liver disease, sera from 263 patients with severe alcoholic hepatitis and/or cirrhosis were analyzed for hepatocyte growth factor (HGF) and α‐fetoprotein (AFP). HGF concentration was elevated above healthy controls in 95% of the patients (median level = 2.4 ng/ml), whereas AFP tended to be depressed below controls (median level = 4.1 ng/ml). Correlations with parameters of liver injury (i.e., ascites, encephalopathy, AST bilirubin, and protime) all showed a more significant correlation with HGF concentrations than those of AFP. Patients with HGF levels below the mean (4 ng/ml) exhibited significantly better survival (median survival = 35 months vs. 8.5 months for those with HGF ≥4 ng/ml; p= 0.007). Serum HGF levels were associated with various specific histologic features of alcoholic hepatitis that included, but were not exclusively related to, necrosis.
Problems in Pharmacokinetic Analysis of Alcohol Disposition: A Trial of the Bayesian Least‐Squares Method
Authors: Fujimiya Tatsuya , Uemura Koichi , Ohbora Yumiko , Komura Setsuo
Published: April 2006

The technical problems of the pharmacokinetic analysis of alcohol disposition were studied using the Michaelis‐Menten elimination kinetic model. This model was defined by two forms of equations: differential and integrated, with the latter being derived by integration of the differential equation. We compared the parameter values, estimated by one‐line curve‐fitting, using these two equation forms. We concluded that, for the kinetic analysis of alcohol disposition, curve‐fitting with the differential equation was superior to that with the integrated equation. We also studied the methodological problems involved in one‐line fitting. The ordinary least‐squares (OLS) method was compared with the Bayesian least‐squares (BLS) method. Correlation between the Vmax and β (ethanol elimination rate) values, and between the Vmax and Km values, was seen when the parameter values were estimated by the OLS method. These results suggested that one‐line fitting by the OLS method was not adequate for Michaelis‐Menten‐type elimination kinetic analysis. BLS analysis resulted in no correlation between the estimated parameter values that did not change with the level of the dose. The BLS method seemed to be more useful than the OLS method for the estimation of individual pharmacokinetic parameter values.
Evidence that Cytochrome P‐4502E1 Contributes to Ethanol Elimination at Low Doses: Effects of Diallyl Sulfide and 4‐Methyl Pyrazole on Ethanol Elimination in the Perfused Rat Liver
Authors: Matsumoto Hiroshi , Matsubayashi Keiko , Fukui Yuko
Published: April 2006

The roles of cytochrome P‐4502E1 and alcohol dehydrogenase (ADH) on ethanol (EtOH) hepatic elimination was examined in the perfused rat liver. EtOH concentration‐time curves of outflow after instantaneous administration (0.46 mg) through the portal vein with or without perfusion of diallyl sulfide (DAS), a selective cytochrome P‐4502E1 inhibitor, and/or 4‐methyl pyrazole (4‐MP), a classical ADH inhibitor, were analyzed by the statistical moment analysis and the compartment dispersion model. Recovery ratios obtained by moment analysis significantly changed with perfusion of inhibitors (p < 0.01). Values of the hepatic volume of distribution and the relative dispersion were significantly higher by the perfusion of DAS and 4‐MP (p < 0.01). In the two‐compartment dispersion model, the partition ratio (K') and the first‐order elimination constant (Ke) were decreased significantly by DAS (p < 0.05). By the addition of 4‐MP, the blood volume of distribution (VB) and the backward partition rate constant (k21) were increased significantly (p < 0.05). Ke values were decreased significantly to 0 (p < 0.001). The decrease of elimination rates by DAS and/or 4‐MP shows the inhibition of metabolic pathways. The change of VB and k21 caused by DAS and 4‐MP indicates that EtOH taken into hepatic tissues was not metabolized and flowed out into the perfusates. Inhibition rates calculated from the efficiency number with addition of DAS and DAS + 4‐MP were 40.7 and 99.3%. Therefore, cytochrome P‐4502E1 and ADH accounted for 40 and 60% of the hepatic EtOH elimination at low doses.
Acetaminophen Metabolism in Patients with Different Cytochrome P‐4502E1 Genotypes
Authors: Ueshima Yasuhiro , Tsutsumi Mikihiro , Takase Shujiro , Matsuda Yoshiro , Kawahara Hiromu
Published: April 2006

Cytochrome P‐450 (CYP) 2E1 is the major ethanol‐oxidizing enzyme of the nonalcohol dehydrogenase metabolic pathway in the liver. Recently, the presence of genetic polymorphisms of this enzyme was confirmed. In this study, to clarify the influence of CYP2E1 genotype on alcohol metabolism, we analyzed acetaminophen metabolism in subjects with different CYP2E1 genotypes. In normal subjects, a half‐life of acetaminophen from blood was the longest in type A (c1/c1) and was the shortest in type C (c2/c2). The elimination rate in type C was more than twice that of type A and type B (c1/c2). In type A, both half‐life and elimination rate of acetaminophen were not different between patients with noncirrhotic alcoholic liver disease within 1 week after abstinence and in normal subjects. In one patient with minimal change, there were no differences in both half‐life and elimination rate within 1 and 6 weeks after abstinence. On the other hand, in type B, half‐life was shorter and the elimination rate was greater in alcoholic noncirrhotic patients within 1 week after abstinence than in alcoholic patients with type A and in normal subjects with type B. In type B, half‐lives were shorter, and the elimination rates were greater in patients with alcoholic liver disease within 1 week after abstinence than 4 to 6 weeks after abstinence. These results suggest the possibility that alcohol metabolism in individuals with the c2 gene may be greater than those with the c1 gene, and that the induction of CYP2E1 by ethanol in type B may occur more markedly than that in type A, although the sample number is too small to obtain final conclusions.
Effects of Cimetidine on Blood Ethanol Levels after Alcohol Ingestion and Genetic Polymorphisms of σ‐Alcohol Dehydrogenase in Japanese
Authors: Kawashima Osamu , Yamauchi Masayoshi , Maezawa Yoshihiko , Toda Gotaro
Published: April 2006

Administration of cimetidine, an H2‐receptor antagonist, increases blood alcohol concentrations. This has been attributed to decreased gastric first‐pass metabolism of ethanol caused by cimetidine's inhibitory effect on gastric alcohol dehydrogenase (σ‐ADH) activity. Molecular studies on σ‐ADH showed that a point mutation might occur at position 287 (G → T) of the σ‐ADH gene in Japanese deficient type of σ‐ADH activity. To clarify the relationship between firstpass metabolism of ethanol and polymorphism of σ‐ADH, we analyzed the nucleotide sequence at positions 287 and 294 of σ‐ADH in 11 individuals who were administered ethanol orally before and after treatment with cimetidine. Higher blood ethanol levels after cimetidine administration were found in 4 of 11 cases (group A), whereas high blood ethanol levels were observed in 7 of 11 cases (B group), irrespective of cimetidine administration. Genetic polymorphisms at position 287 and 294 were not observed in all subjects. Even in 59 Japanese men with various alcoholic liver diseases, no polymorphisms at position 287 were observed by restriction‐length polymorphisms with Ava II digestion after polymerase chain reaction.
Effect of Vitamin E Deficiency on Inhibition of Liver Regeneration by Long‐Term Administration of Alcohol
Authors: Tanaka Takashi , Goto Yasutaka , Imano Miki , Asai Hirohide , Yamada Takao , Kawai Shuji , Kunitoh Satoru , Kondo Kyoko , Yamashita Terumi , Monna Takeyuki , Nishiguchi Shuhei , Kuroki Tetsuo , Otani Shuzo
Published: April 2006

The effects of vitamin E (VE) deficiency on liver regeneration suppressed by long‐term administration of alcohol were studied. Male rats were divided into two groups: the alcohol group and the control group. In addition, each group was subdivided into two groups according to the presence or not of VE. Altogether, four groups were provided: a group maintained on the VE‐deficient alcohol diet (group EA), a group maintained on the VE‐deficient control diet (group EC), a group maintained on the ordinary alcohol diet (group A), and a group maintained on the ordinary control diet (group C). After pair‐feeding for 6 weeks, partial hepatectomy was performed to determine the ornithine decarboxylase (ODC) activity, polyamine levels, lipid peroxide levels, and DNA synthesis. DNA synthesis at 24 hr after partial hepatectomy was suppressed significantly in the alcohol administration group, regardless of the presence or not of VE. DNA synthesis at 48 hr after partial hepatectomy tended to show low values in group EA, compared with group A. As for the hepatic ODC activity, group EA showed the lowest value at 4 hr after partial hepatectomy. Of polyamines, the putrescine level in group EA at 4 hr after partial hepatectomy was significantly low, compared with the other three groups. The levels of spermidine and spermine decreased by long‐term administration of alcohol, but the effect of VE deficiency was not found. The lipid peroxide level increased significantly in the VE‐deficient diet administration group, but the effect of alcohol administration was not found. These results suggested that the decrease in putrescine after ODC suppression by VE deficiency in addition to the decrease in spermidine and spermine caused by long‐term alcohol administration were concerned with suppression of DNA synthesis later.
Abnormality in Membrane Fatty Acid Compositions of Cells Measured on Erythrocyte in Alcoholic Liver Disease
Authors: Shiraishi Koichi , Matsuzaki Shohei , Itakura Masaru , Ishida Hideyuki
Published: April 2006

It has been proven that the fatty acids of esterified phospholipids in the cell membrane play an important role in membrane fluidity. Our previous in vitro experiment indicated that the impairment of erythrocyte membrane fluidity might be largely because of the change in fatty acids. The aim of this study is to clarify changes of cell membrane fatty acids in more detail in relation to various stages and pathology of alcoholic liver disease. For the analysis, erythrocyte membranes were exploited on the assumption that their fatty acid compositions may be similar to those of other organs. In alcoholic liver disease, unsaturated fatty acids in the erythrocyte membrane decreased and saturated fatty acids increased. Consequently, the unsaturated fatty acid/saturated fatty acid ratio decreased significantly. When fractions of saturated fatty acids were studied, myristic acid (C14:0) increased markedly in the alcoholic group, and the increase was striking particularly in the cases of alcoholic hepatitis concurrently with hemolysis. Palmitic acid (C16:0) also tended to increase in the alcoholic liver disease group. A longer chain saturated fatty acid, stearic acid (C18:0), showed a moderate but significant increase in the alcoholic fatty liver and hepatic fibrosis group, but it decreased significantly in the alcoholic liver cirrhosis, as with the finding in viral liver cirrhosis. As with unsaturated fatty acids, linoleic acid (C18:2), arachidonic acid (C20:4), and eicosapentanoic acid (C20:5) decreased significantly. The arachidonic acid/linoleic acid ratio, which indicates microsomal elongation activity of liver cells, was found to be broadly distributed. No significant change was found in each group of alcoholic liver disease. However, the cases showing a decrease in this ratio had severe hepatic dysfunction concurrently. Thrombogenic Index, serving as an indicator for fatty acids in food, and that is concerned with formation of thrombus, was studied, using fatty acid fractions of the erythrocyte membrane. The index was significantly increased in alcoholic liver disease. It was suggested that the chronic alcohol intake and the resultant liver diseases might enhance the abnormality of the membrane fatty acid composition. These changes may affect cell membrane fluidity and eventually metabolic functions of the cell.
Role of Albumin and High‐Density Lipoprotein as Endotoxin‐Binding Proteins in Rats with Acute and Chronic Alcohol Loading
Authors: Kitano Hiroyuki , Fukui Hiroshi , Okamoto Yasuyuki , Kikuchi Eiryou , Matsumoto Masami , Kikukawa Masaji , Morimura Masafumi , Tsujita Sigenobu , Nagamoto Issei , Nakatani Toshiya , Takaya Akira , Tsujii Tadasu
Published: April 2006

In the present study, the role of albumin and high‐density lipoprotein (HDL) as endotoxin (Et)‐binding proteins in chronically alcohol‐fed rats was studied. In acute ethanol‐loaded rats, the Et clearance in the blood was slightly prolonged, and the amount of albumin and HDL‐bound Et in the blood was markedly increased. In chronic ethanol‐loaded rats, the Et clearance was significantly faster than that in the control, and HDL‐bound Et was increased. In the chronic ethanol‐fed rats with an additional 5 g/kg body weight of ethanol load, the Et clearance was much prolonged, and blood tumor necrosis factor and ALT was elevated, when HDL‐bound Et was not further increased. Et‐binding capacity of total proteins, albumin, and HDL in the hepatocyte culture medium were increased when the Kupffer cells were preincubated in the medium containing ethanol, and the resultant culture supernatant was added to the hepatocyte culture system. In the culture experiment in the chronic ethanol‐loaded rats, such increases were not observed. These results suggest that the increase in Et‐binding capacity of HDL and albumin may serve as a protective mechanism against Et in chronic ethanol‐loaded rats. An addition of high‐dose ethanol to these rats may lead to impaired Et binding and inactivation, which may finally result in increased endotoxicity.
Mitochondrial ALDH Polymorphism Affects Ethanol‐Derived Acetate Disposition in Wistar Rats
Authors: Matsumoto Hiroshi , Matsubayashi Keiko , Fukui Yuko
Published: April 2006

We studied the relationship between polymorphism of aldehyde dehydrogenase (ALDH) and ethanol and acetate kinetics in male Wistar rats. Blood ethanol and acetate concentration time curves after intravenous bolus administration of 1 g/kg of ethanol were estimated by moment analysis. ALDH isozymes in hepatic subcellular fractions were detected by isoelectric focusing (IEF)‐ Blood acetate profiles were divided into two patterns: one‐peak type and two‐peak type. IEF studies on ALDH isozymes in subcellular fractions showed polymorphism of cytosolic and mitochondrial ALDHs. Polymorphism patterns of ALDH2 corresponded with patterns of blood acetate profiles. Significant differences in mean residence time of acetate and the ratio of area under curves (AUCs) of acetate to ethanol (AUCacetate/AUCEtoH) occurred between different IEF patterns of mitochondrial low Km ALDH (ALDH2). Therefore, it was clarified that ALDH2 polymorphism affects ethanol‐derived acetate disposition in Wistar rats. Similarity of AUC values of acetate considered, these observations suggest that ALDH2 polymorphism results in change of effects of acetate and acetate‐generated adenosine on the central nervous system and other organs during chronic ethanol consumption.