bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of ALDH2 and CYP2E1 Gene Polymorphisms on Drinking Behavior and Alcoholic Liver Disease in Japanese Male Workers
Authors: Okamoto Kinya , Murawaki Yoshikazu , Yuasa Isao , Kawasaki Hironaka 
Published: April 2006

Aims: We examined the relationships of ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease in Japanese male workers.Methods: Two hundred and eighty‐seven Japanese men were selected from one metal company to adjust for similar economic and social backgrounds. Drinking behavior was assessed from a self‐assessment questionnaire. Genotypes of ALDH2 and CYP2E1 were analyzed with the polymerase chain reaction‐single strand conformation polymorphism and with the polymerase chain reaction‐restriction fragment length polymorphism, respectively.Results: The frequency of the ALDH2 genotype was 55% for typical homozygotes, 42% for heterozygotes, and 4% for atypical homozygotes. The frequency of the CYP2E1 genotype was 62% for c1 homozygotes, 35% for heterozygotes, and 3% for c2 homozygotes. The ALDH2 genotype closely influenced drinking habits, but not the CYP2E1 genotype. Among habitual drinkers, ALDH2 typical homozygotes consumed significantly larger amounts of ethanol than ALDH2 heterozygotes, whereas CYP2E1 genotypes did not influence daily alcohol consumption. Sixteen men (5.6%) were diagnosed with alcoholic liver disease. In terms of ALDH2 genotypes, 12 cases (7.6%) were typical homozygotes and 4 (3.4%) were heterozygotes, whereas the incidence of alcoholic liver disease was not different between c1/c1 homozygotes and c1/c2 heterozygotes. When the interactive contribution of the ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease were examined, there were no significant differences in the CYP2E1 genotype among the subjects with the same ALDH2 genotype.Conclusion: The ALDH2 genotype is strongly associated with individual alcohol drinking behavior and the development of alcoholic liver disease in Japanese male workers, but the CYP2E1 genotype is not.
Effects of Chronic Alcohol Consumption on Hepatic Poly‐ADP‐Ribosylation in the Rat
Authors: Nomura Fumio , Yaguchi Masae , Itoga Sakae , Noda Masatoshi 
Published: April 2006

Background: Poly‐adenosine diphosphate (ADP)‐ribosylation is involved in a variety of biological processes, which include DNA repair, malignant transformation, and apoptosis. It is of interest how this reaction is altered after long‐term alcohol intake. Therefore, we determined long‐term alcohol effects on hepatic poly‐ADP‐ribosylation in the rat.Methods: Male Sprague Dawley® rats (four pairs) were pair‐fed a nutritionally adequate liquid diet that contained ethanol as 36% of total energy and an isocaloric control diets for 4 weeks. Liver tissue homogenates and nuclear fractions were subjected to ADP‐ribosylation with [32P]nicotinamide adenine dinucleotide. The ADP‐ribosylated proteins were separated by SDS‐PAGE, followed by autoradiography. Expression of poly‐ADP‐ribose polymerase (PARP) also was evaluated by Western blotting.Results: Incubation of rat liver homogenates in ADP‐ribosylation reaction mixture resulted in a radiolabeling of a 116 kDa protein, most likely auto‐ribosylation of PARP. This poly‐ADP‐ribosylation was increased significantly (p < 0.025) after long‐term alcohol intake. This alcohol effect was reproducible in nuclear fractions as well. Expression levels of PARP, however, were comparable between alcohol‐fed rats and their pair‐fed controls.Conclusion: Poly‐ADP‐ribosylation, an important posttranslational modification of nuclear proteins, was increased significantly after chronic alcohol consumption in the rat.
Kupffer Cell Sensitization by Alcohol Involves Increased Permeability to Gut‐Derived Endotoxin
Authors: Enomoto Nobuyuki , Ikejima Kenichi , Yamashina Shunhei , Hirose Miyoko , Shimizu Hidetake , Kitamura Tsuneo , Takei Yoshiyuki , Sato Nobuhiro , Thurman Ronald G. 
Published: April 2006

Background: Studies with gut sterilization and Kupffer cell inactivation support the hypothesis that endotoxin and Kupffer cells are involved in mechanisms of alcohol‐induced liver injury. Recently, we found that Kupffer cells isolated from rats treated only once with ethanol were sensitized to endotoxin 24 hr later. Moreover, we established a new, simple animal model of ethanol hepatotoxicity based on Kupffer cell sensitization. The purpose of this study was to determine the mechanisms by which alcohol sensitizes Kupffer cells to lipopolysaccharide (LPS).Methods: Female Wistar rats were given ethanol (5 g/kg body weight) once every 24 hr intragastrically, and ethanol concentration, ethanol elimination, and portal vein endotoxin were measured. Gut permeability was measured in isolated segments of ileum by translocation of horseradish peroxidase. Kupffer cells were isolated 24 hr after ethanol administration in vivo and were cultured in RPMI 1640 with 10% fetal bovine serum. After the addition of LPS, intracellular Ca2+ was measured by using a microspectrofluorometer with the fluorescent indicator fura‐2, and tumor necrosis factor (TNF)‐α was measured by enzyme‐linked immunosorbent assay. CD14 was evaluated by Western analysis.Results: Ethanol levels exhibited a cyclic pattern in ethanol‐treated rats. Similar results were obtained in groups given ethanol and antibiotics for 4 weeks. Rates of alcohol elimination were around 3.5 mmol/kg/hr in control rats. After 4 weeks of ethanol treatment with or without antibiotics, elimination rates were not changed. Translocation of horseradish peroxidase was increased about 3‐fold in gut segments by treatment with ethanol. This increase was not altered by treatment with antibiotics. Moreover, portal vein endotoxin levels were increased from nearly undetectable levels to 80 pg/ml in plasma of rats treated with ethanol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells from rats treated with ethanol for 4 weeks, CD14, LPS‐induced intracellular Ca2+, and TNF‐α all were increased. These phenomena were blocked by antibiotics.Conclusions: Kupffer cells isolated from rats treated with ethanol for 4 weeks exhibit sensitization to LPS. It is likely that increased permeability of the gut is a prominent event that leads to alcoholic liver injury.
Effect of Fenofibrate on Fatty Liver in Rats Treated With Alcohol
Authors: Tsutsumi Mikihiro , Takase Shujiro 
Published: April 2006

Background: Although fatty liver and hyperlipemia are common in chronic alcoholics, there is no practical approach to prevent alcoholic fatty liver. Recently, it has been reported that fibrates bind to peroxisome proliferator‐activated receptor‐α and induce β‐oxidation enzymes of fatty acid in mitochondria. In this study, we investigated the effect of fenofibrate, one of the fibrates, on fatty liver in rats induced by chronic alcohol feeding. Furthermore, we studied the effect of fenofibrate on hyperlipemia in patients with alcoholic fatty liver.Methods: Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 4 weeks. Fenofibrate was administered orally with the liquid diets for 4 weeks at a concentration of either 0, 5, or 30 mg/kg body weight/day. As a pilot study, eight patients with alcoholic fatty liver were treated with 200 mg/day of fenofibrate for 4 weeks.Results: After fenofibrate administration, fatty degeneration of liver was not observed in three of the five rats treated with 5 mg and in all rats treated with 30 mg of fenofibrate. Hepatic triglyceride content was decreased significantly in rats treated with 30 mg of fenofibrate compared with the rats not treated with fenofibrate. Serum triglyceride and total cholesterol levels also were decreased after treatment with fenofibrate. In eight alcoholic patients treated with 200 mg of fenofibrate for 4 weeks, serum triglyceride level decreased significantly compared with the levels before treatment. All patients continued alcohol consumption during fenofibrate administration.Conclusion: The results of the present investigation suggest that fenofibrate may be useful to prevent alcoholic fatty liver. Further studies with larger numbers of patients are necessary to obtain definitive results.
Gene Coding Variant in Cas1 Between the C57BL/6J and DBA/2J Inbred Mouse Strains: Linkage to a QTL for Ethanol‐Induced Locomotor Activation
Authors: Xu Yan , Demarest Kristin , Hitzemann Robert , Sikela James M. 
Published: April 2006

Background: Among some (e.g., DBA/2J or D2) but not all (C57BL/6J or B6) inbred strains of mice, ethanol has a marked psychostimulant effect. Intercrosses formed from the D2 and B6 strains have been used to detect quantitative trait loci (QTLs) for this phenotype. The major QTL is found at the mid‐region of chromosome 2 (Demarest et al., 1999). This QTL has also been detected in heterogeneous stock mice (Demarest et al., 2001). A potential candidate gene in this region is Cas1, which codes for catalase. The current studies were conducted to determine (a) if there was difference in the open reading frame (ORF) of Cas1 between the D2 and B6 strains; (b) if a difference was found, was it likely that the difference had functional effects; and (c) if it could be established that Cas1 meets the criteria for QTL to gene.Methods: The open reading frame (ORF) of Cas1 was sequenced in both the D2 and B6 mouse strains. A single polymorphism was found between the strains (see below); the strain distribution pattern for this polymorphism was determined in the 36 strains of the B6XD2 (BXD) recombinant inbred (RI) series. These data were used to map the position of Cas1 as described by Cudmore et al. (1999).Results: The only difference between the D2 and B6 strains in the coding region was found at #349, G–>A. This will result in a difference in the amino acid sequence between the strains at amino acid #117–alanine is found in the D2 strain while threonine is found in the B6 strain. The RI strain distribution pattern for this polymorphism was used to determine the relative placement of Cas1. The estimate suggests that Cas1 is flanked by D2Mit12 and D2Mit43 and relative to D2Mit94 (which was set at 47 cM), Cas1 is located at approximately 57 cM, confirming previous estimates (see http://www.jax.org).Conclusions: Pharmacological data (Correa et al., 2001) strongly support the idea that Cas1 meets the criteria for QTL to gene. However, based on the mapping data, Cas1 is clearly not included in the QTL for heterogeneous stock mice. Finally, other genetic data suggest that the polymorphism is not sufficient to generate the QTL.
Brief Physician Advice for Problem Drinkers: Long‐Term Efficacy and Benefit‐Cost Analysis
Authors: Fleming Michael F. , Mundt Marlon P. , French Michael T. , Manwell Linda Baier , Stauffacher Ellyn A. , Barry Kristen Lawton 
Published: April 2006

Background: This report describes the 48‐month efficacy and benefit‐cost analysis of Project TrEAT (Trial for Early Alcohol Treatment), a randomized controlled trial of brief physician advice for the treatment of problem drinking.Methods: Four hundred eighty‐two men and 292 women, ages 18–65, were randomly assigned to a control (n= 382) or intervention (n= 392) group. The intervention consisted of two physician visits and two nurse follow‐up phone calls. Intervention components included a review of normative drinking, patient‐specific alcohol effects, a worksheet on drinking cues, drinking diary cards, and a drinking agreement in the form of a prescription.Results: Subjects in the treatment group exhibited significant reductions (p < 0.01) in 7‐day alcohol use, number of binge drinking episodes, and frequency of excessive drinking as compared with the control group. The effect occurred within 6 months of the intervention and was maintained over the 48‐month follow‐up period. The treatment sample also experienced fewer days of hospitalization (p= 0.05) and fewer emergency department visits (p= 0.08). Seven deaths occurred in the control group and three in the treatment group. The benefit‐cost analysis suggests a $43,000 reduction in future health care costs for every $10,000 invested in early intervention. The benefit‐cost ratio increases when including the societal benefits of fewer motor vehicle events and crimes.Conclusions: The long‐term follow‐up of Project TrEAT provides the first direct evidence that brief physician advice is associated with sustained reductions in alcohol use, health care utilization, motor vehicle events, and associated costs. The report suggests that a patient's personal physician can successfully treat alcohol problems and endorses the implementation of alcohol screening and brief intervention in the US health care system.
Alcohol Consumption Attenuates Febrile Responses to Lipopolysaccharide and Interleukin‐1β in Male Rats
Authors: Taylor Anna N. , Tio Delia L. , Heng Ngy S. , Yirmiya Raz 
Published: April 2006

Background: Chronic and acute alcohol use exert profound modulatory effects on the immune system which manifest as impaired host defense against infections. An important feature of this response is the interaction between the immune and the central nervous systems. This study investigated the effects of 14 days of alcohol exposure on cytokine‐mediated neuroimmune interactions that affect the febrile component of the host‐defense response.Methods: Adult male rats were fed a liquid diet containing ethanol (EtOH, 5% w/v) for 14 days. Pair‐fed and normal chow‐ and water‐fed rats served as controls. Continuous biotelemetric recordings of body temperature and locomotor activity commencing after 14 days of EtOH feeding were used to determine the effects of chronic EtOH on the circadian pattern of temperature and activity, on the febrile response to intraperitoneal (ip) administration of lipopolysaccharide (LPS) and interleukin (IL)‐1β, and on fever induced by IL‐1β administered intracerebroventricularly. We also examined the effects of EtOH consumption on LPS‐induced hypothalamic production of the pyrogenic cytokines IL‐1β and tumor necrosis factor‐α (TNFα) and on the blood levels of IL‐1β, TNFα, IL‐6, adrenocorticotropin, and corticosterone at 2, 4, and 6 hr after ip LPS.Results: Fourteen days of EtOH consumption blunted the circadian increases in temperature and activity that normally occur in the dark phase of the light/dark cycle without affecting light‐phase temperature or activity. EtOH consumption attenuated fever induced by LPS or IL‐1β administered ip during the light phase and significantly reduced hypothalamic production of IL‐1β. LPS‐induced increases in hypothalamic TNFα and blood cytokines, adrenocorticotropin, and corticosterone were unaffected. Central administration of IL‐1β produced a normal febrile response in chronic‐EtOH rats.Conclusions: The attenuated LPS‐ and IL‐1β–induced febrile responses in EtOH‐consuming rats and the corresponding deficit in hypothalamic production of IL‐1β suggest that alcohol may impair IL‐1β–mediated neuroimmune communication.
Acute Alcohol Intoxication Suppresses the CXC Chemokine Response During Endotoxemia
Authors: Zhang Ping , Bagby Gregory J. , Boé Darren M. , Zhong Qiu , Schwarzenberger Paul , Kolls Jay K. , Summer Warren R. , Nelson Steve 
Published: April 2006

Background: CXC chemokines play an important role in host defense against infections. Alcohol is a frequently abused drug that inhibits numerous immune functions of the host. This study investigated the effects of alcohol on CXC chemokine macrophage inflammatory protein‐2 (MIP‐2) and cytokine‐induced neutrophil chemoattractant (CINC) responses in rats challenged with intravenous lipopolysaccharide (LPS).Methods: Acute ethanol intoxication was induced by an intraperitoneal injection of 20% alcohol (5.5 g/kg). Thirty minutes thereafter, LPS (500 μg/kg) was administered intravenously. In another set of experiments, rats were intravenously administered an anti‐tumor necrosis factor‐α (TNFα) neutralizing antibody (10 mg per rat) 2 hr before the LPS challenge.Results: At 1 and 2 hr after the LPS challenge, MIP‐2, CINC, and TNFα concentrations in the plasma were significantly increased. Alcohol intoxication suppressed the MIP‐2, CINC, and TNFα responses in the bloodstream during endotoxemia. Alcohol also suppressed the increase in plasma chemotactic activity and polymorphonuclear leukocyte adhesion molecule expression in rats with endotoxemia. MIP‐2 and CINC messenger RNA (mRNA) expression was significantly increased 1 hr after endotoxemia in the lung, liver, and spleen. Alcohol suppressed the up‐regulation of MIP‐2 mRNA expression in all of these organs and CINC mRNA expression in the lungs of rats with endotoxemia. TNFα neutralization minimally inhibited plasma CINC and MIP‐2 responses during endotoxemia and did not suppress the increase in plasma chemotactic activity.Conclusions: These results show that alcohol suppresses the systemic CXC chemokine response to LPS, which is not primarily mediated by ethanol‐induced suppression of TNFα. This disruption of host‐defense function may serve as one mechanism underlying the increased risk of infectious diseases in hosts who abuse alcohol.
A Role for Interleukin‐10 in Alcohol‐Induced Liver Sensitization to Bacterial Lipopolysaccharide
Authors: Hill Daniell B. , D'Souza Nympha B. , Lee Eun Y. , Burikhanov Ravshan , Deaciuc Ion V. , de Villiers Willem J. S. 
Published: April 2006

Background: Proinflammatory cytokines play an important role in alcohol‐induced liver injury. The role of anti‐inflammatory cytokines in the initiation and progression of alcoholic liver disease has received little attention. This study tested the hypothesis that an imbalance exists between pro‐ and anti‐inflammatory cytokines in the liver during chronic exposure to alcohol. Alcohol exposure results in predominantly proinflammatory cytokine secretion and liver injury.Methods: IL‐10 knock‐out and their C57BL/6J counterpart wild‐type mice were fed alcohol in drinking water for 7 weeks. At the end of alcohol feeding, Gram‐negative bacterial lipopolysaccharide (LPS) was administered, and the animals were killed after 3 and 8 hr. Liver histology, plasma alanine aminotransferase and aspartate aminotransferase activity, tumor necrosis factor‐α, interleukin (IL)‐1β and IL‐10 levels, and liver cytokine messenger RNA levels were measured.Results: Alcohol feeding and LPS treatment did not change plasma enzyme activity levels in wild‐type mice. In the IL‐10 knock‐out mice, LPS alone increased aspartate aminotransferase and alanine aminotransferase enzyme activity, and this was potentiated by alcohol. Alcohol induced liver steatosis in both wild‐type and knock‐out mice. LPS markedly enhanced the histological effects further, especially in the knock‐out mice, with the emergence of focal necrosis, polymorphonuclear infiltration, and microabscesses in the liver. Plasma tumor necrosis factor‐α and IL‐1β levels were not affected by alcohol alone. Proinflammatory cytokine levels were increased by LPS and further enhanced by alcohol treatment, particularly in the IL‐10 knock‐out mice. IL‐10 plasma levels in the wild‐type animals were down‐regulated by alcohol. Changes in liver cytokine messenger RNA paralleled those seen in plasma cytokine levels.Conclusions: Alcohol‐induced liver sensitization to LPS in wild‐type mice may involve down‐regulation of IL‐10. This anti‐inflammatory cytokine, known for its hepatoprotective effects, is secreted simultaneously with proinflammatory cytokines. IL‐10 may also limit alcohol‐induced liver damage by counteracting the effects of proinflammatory cytokines.
Suggestive Linkage on Chromosome 1 for a Quantitative Alcohol‐Related Phenotype
Authors: Dick Danielle M. , Nurnberger John , Edenberg Howard J. , Goate Alison , Crowe Ray , Rice John , Bucholz Kathleen K. , Kramer John , Schuckit Marc A. , Smith Tom L. , Porjesz Bernice , Begleiter Henri , Hesselbrock Victor , Foroud Tatiana 
Published: April 2006

Background Alcohol dependence is a clinically and etiologically heterogeneous disorder. Accordingly, a variety of subtypes of alcohol‐dependent individuals have been proposed, and multiple operational definitions of alcohol use, abuse, and dependence have been used in linkage analyses directed toward detecting genes involved in alcohol use and problems. Here, we develop quantitative phenotypes that characterize drinking patterns among both alcoholic and nonalcoholic subjects, and use these phenotypes in subsequent linkage analyses.Methods More than 9000 individuals from alcoholic and control families were administered a semistructured interview and personality questionnaire as part of the initial stage of the Collaborative Study on the Genetics of Alcoholism (COGA). A principal component analysis was conducted on items that captured many of the dimensions of drinking and related behaviors, including aspects of alcohol use, antisocial behavior and affective disturbance when drinking, and personality. Factor scores were computed for all individuals. Nonparametric linkage analyses were conducted on these factor scores, in the initial COGA sample consisting of 987 individuals from 105 extended families, and in a replication sample consisting of 1295 individuals from 157 extended families.Results Three factors were identified, accounting for 68% of the total variance. The most promising regions of linkage appeared for factor 2, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance. Chromosome 1 yielded consistent evidence of linkage in both samples, with a maximum lod score of 3.3 when the samples were combined for analysis. Consistent suggestion of linkage also was found to chromosome 15.Conclusions Developing novel phenotypes that more accurately model the effect of influential genes may help efforts to detect genes involved in complex disorders. Applying principal component analysis in the COGA sample provided support for some regions of linkage previously reported in COGA, and identified other new, promising regions of linkage.
Monte Carlo Simulation of an Ethanol Pharmacokinetic Model
Authors: Whitmire David , Cornelius Larry , Whitmire Paula 
Published: April 2006

Background One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology.Methods To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the χ2 function.Results Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79‐fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 ± 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH.Conclusions Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.