Yedy Israel - US grants

Liver cell death in alcoholic liver disease occurs predominantly in the centrilobular (periacinar) areas of the liver that (a) are exposed to low oxygen tensions and (b) are most active in transforming some substances into toxic electrophiles. Glutathione (GSH), known to protect against these toxic substances, is lowest in the centrilobular zone. Acute ethanol administration leads to marked increases in liver oxygen consumption and in splanchnic blood flow. These effects can be produced by the administration of glucagon. It is hypothesized that the effects of ethanol on splanchnic oxygen consumption and on splanchnic blood flow are mediated by glucagon, the levels of which are markedly increased by acute ethanol administration. Since glucagon is released into the portal blood and is largely cleared by the liver, moderate increases in glucagon, at low levels of ethanol, are expected to result in increases in liver oxygen consumption that are not accompanied by increases in splanchnic blood flow. Studies will be conducted to test this hypothesis. Acute ethanol administration markedly reduces liver GSH levels, an effect that is also shared by glucagon. The mechanism(s) of liver GSH depletion induced by ethanol, and the centrilobular or periportal localization of this effect will be investigated. The compensatory mechanisms for liver GSH repletion following chronic alcohol administration will also be studied. In human alcoholics who develop alcoholic liver disease the compensatory mechanisms for GSH repletion would appear to be deficient. We postulate that chronic alcohol treatment induces mechanisms that lead to an increased availability of GSH precursors to the liver. One such mechanism is the transformation of methionine into cysteine and a second one is the operation of gamma glutamyl transferase as a compensatory mechanism to recover GSH precursors from extracellular GSH. Hepatic gamma glutamyl transferase is markedly and consistently increased by chronic ethanol consumption but the significance of such increase is not known. The studies investigate the physiological role of this enzyme in the transport of aminoacids in the liver of animals fed alcohol chronically as well as in controls.

acetaldehyde; alcoholism /alcohol abuse; chemical addition;

A number of studies have indicated the potential of the primary care physician in the identification and treatment of the alcohol abuse patient. About one in five patients visiting a primary care physician presents an alcohol abuse problem. Nevertheless, the majority of family physicians do not diagnose and treat alcohol abuse. Recent studies indicate that at early stages of alcohol abuse, interventions delivered by different professionals to reduce hazardous alcohol consumption are highly effective. Brief interventions which include follow-up and biofeedback (where continuous information is provided to the patient on his/her biochemical tests) have been shown to be most successful in reducing morbidity in the alcohol abuse patient. The primary purpose of the study is to test the general hypothesis that early identification of alcohol abuse by family physicians in private practice, coupled with a brief intervention and biofeedback by a physician-nurse team significantly reduces morbidity associated with alcohol abuse. The project involves the identification of alcohol abuse by means of a non-obtrusive identification instrument acceptable to family physicians, followed by patient referral for a brief intervention by a life-style nurse. Patients are randomly assigned to different intervention groups, including a minimal intervention group. Objective outcome measures are determined at 12 and 24 months. It is hypothesized that (i) a brief behavioral self control intervention including follow-up results in superior outcome, compared with a control minimal intervention; (ii) when controlled for follow-up frequency, patients receiving biofeedback present improved outcomes compared with patients receiving no biofeedback. The study also aims at (iii) assessing the rate of identification of alcohol abuse in medical primary care and (iv) assessing the rate of successful referral to an intervention program for patients identified by physicians as at risk of alcohol abuse. The long term goal is to develop viable community models for the prevention of alcohol abuse and alcohol dependence, which staff with the family physician in private practice.

free radical oxygen; adduct; biomarker; alcoholic beverage consumption; ethanol; glutathione; oxidation reduction reaction; Kupffer's cell; haptens; body fluids; covalent bond; aminoacid; polymers; high performance liquid chromatography; laboratory rat; laboratory rabbit; laboratory mouse; nuclear magnetic resonance spectroscopy; mass spectrometry;

Recent studies indicate that the Kupffer cell plays a major role in the production of liver injury induced by a number of hepatotoxins and pathological conditions. Obliteration of Kupffer cells virtually abolishes cell necrosis and inflammation induced by xenobiotics such as ethanol, carbon tetrachloride and acetaminophen. Similarly, liver damage induced by endotoxemia or liver storage prior to transplantation is markedly reduced by experimental conditions that reduce Kupffer cell function. Data suggest that tumor necrosis factor-alpha released by Kupffer cells plays a major role in cell damage. The synthesis of tumor necrosis factor- alpha is initiated by gene-transcription factors, which are activated by oxygen radicals and endotoxin. Tumor necrosis factor-alpha triggers a cytokine cascade involving cytotoxic, inflammatory and fibrogenic mediators. The studies proposed (a) test the hypothesis that triple-helix targeting of the tumor necrosis factor-alpha gene in Kupffer cells results in marked reduction of liver damage induced by a number of hepatotoxins and pathogenic conditions; (b) develop methodologies for the design and delivery of triple-helix forming oligonucleotide drugs into Kupffer cells, for possible therapeutic use. Kupffer cells are specialized in the phagocytic removal of particulate matter from the circulation. Studies in this application utilize this phagocytic action to deliver liposome-entrapped triple-helix antigene oligonucleotides into Kupffer cells. The proposed research is designed to (i) suppress the synthesis of tumor necrosis factor-a and the cytokine transcription factor NF-kappaB in Kupffer cells, (ii) reduce the expression of genes involved in the generation of oxygen-radicals in Kupffer cells, and (iii) test the protection afforded by triple-helix drugs against liver necrosis and inflammation induced by the chronic administration of ethanol and other hepatotoxins. Overall, the proposed research investigates at the gene level the existence of central mechanisms of liver injury by new approaches with therapeutic potential for alcoholic liver disease in humans.

Knowledge of the main questions in a field constitutes one of the most important elements determining the success of the scientific endeavor. Optimal interactions between clinical scientists and basic scientists or between social scientists and biomedical scientists occur when common knowledge has developed. Research-to-Practice communication empowers practitioners to become more effective. We will prepare and deliver to postdoctoral fellows, scientists and practitioners a Lecture Series on "Alcohol and Alcohol Effects" as a satellite prior to meetings of the Research Society on Alcoholism (RSA) in years 2000 and 2001. The series, comprising 18-lectures, is divided into two modules: (A) Psychosocial and (B) Biomedical. Attendees will be given a syllabus and the graphic materials of the complete Series in 5 compact disks (CD-ROM), from which transparencies of high quality can be reproduced. In addition to imparting knowledge, this material will help attendees develop smaller lecture series (or parts thereof) at their own Institutions. A group of outstanding scientists and clinicians has been assembled as Series Faculty. They have accepted the task of lecturing in their areas according to the following format: (i) first concepts, (ii) a preference for didactic presentations of well established materials over a complete range of the literature, (iii) not more than 25 slides for a 50 minute lecture, (iv) up to 6-7 slides of their own research, (v) peer review. In the third year the Series will become an "Education at Distance" course via RSA Web-site hyperlink.