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Vishnudutt Purohit, Jag Khalsa, and Jose Serrano.  Mechanisms of alcohol-associated cancers: Introduction and summary of the symposium.  Alcohol 35(3):155-160, April 2005.

Summary:  This article introduces an issue of the journal devoted to an international symposium on Mechanisms of Alcohol-Associated Cancers. The symposium, which was held at Bethesda, Maryland in October 2004, was sponsored by several components of the National Insitutes of Health, including the National Institute on Alcohol Abuse and Alcoholism, the Office of Dietary Supplements, the Office of Rare Diseases, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Diabetes and Digestive and Kidney Diseases. The following mechanisms were examined: (1) production of acetaldehyde, a weak mutagen and carcinogen; (2) induction of cytochrome P450 2E1 and associated oxidative stress and conversion of procarcinogens to carcinogens; (3) depletion of S-adenosylmethionine and, consequently, induction of global deoxyribonucleic acid hypomethylation; (4) induction of increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase–mitogen-activated protein kinase signaling; (5) accumulation of iron and associated oxidative stress; (6) inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness (primarily in breast); and (7) impairment of retinoic acid metabolism. Nicotine may promote carcinogenesis through activation of extracellular signal-regulated kinase/cyclooxygenase-2/vascular endothelial growth factor signaling pathway. NIAAA Glossary Terms:  conference proceedings, cancer, AODR disorder, ethanol, enzymes, cytochrome P450 2E1, biochemical mechanism, oxidative stress, carcinogens, carcinogenesis, DNA, S-adenosylmethionine, acetaldehyde, mutation, guanine nucleotides, regulatory proteins, cell signaling, protein kinases mitogens, retinoic acid, iron, estrogens, gene, nicotine, growth factors, literature review

Linda Morris Brown.  Epidemiology of alcohol-associated cancers.  Alcohol 35(3):161-168, April 2005.

Summary: This paper was presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004. Alcohol, especially in combination with smoking, is a well-established risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus, with 25% to 80% of these cancers being attributable to alcohol. Rates of these cancers in the United States have been decreasing in recent years, possibly because of reduced cigarette smoking and alcohol use. Although epidemiologic evidence has associated chronic alcohol consumption with increased risk of liver cancer, the rising rates of this cancer in the United States are most likely due to the increasing prevalence of chronic hepatitis B and C infections. Epidemiologic evidence has linked light to moderate drinking to colorectal cancers and female breast cancer, both of which are common in developed countries. Although most epidemiologic studies have provided little or no support for a causal relation between light and moderate alcohol use and risk of pancreatic cancer, a possible role of heavy alcohol consumption cannot be ruled out. Further studies of these cancers are needed to clarify the role of type of alcoholic beverage, the role of alcohol concentration, and the dose-response curve at low alcohol concentrations. Future research also should use uniform ways to report alcohol intake and uniform measures for analysis, include the investigation of alcohol-associated cancer risks in U.S. minority populations, enhance experimental work to better understand the underlying mechanisms through which alcohol promotes carcinogenesis, and develop preventive strategies. NIAAA Glossary Terms:  conference proceedings, cancer, AODR disorder, ethanol, risk factors, oral disorder, respiratory airway, larynx, pharynx, esophageal disorder, smoking, chronic AODE, liver disorder, hepatitis B, hepatitis C, epidemiological indicators, epidemiology, breast, light AOD use, moderate AOD use, pancreatic disorder, alcoholic beverage, dose-response relationship, AOD intake per occasion, AOD consumption, minority group, carcinogenesis, causal pathways, prevention strategy, research agenda, literature review

Graham R. Ogden.  Alcohol and oral cancer.  Alcohol 35(3):169-173, April 2005.

Summary: Alcohol, particularly when associated with tobacco use, has been recognized as an important risk factor for oral cancer for nearly 50 years. The combination of drinking and smoking is associated with approximately 75% of upper aerodigestive tract cancers. This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, reviews the potential role of alcohol in the development of oral cancer. The effect of alcohol on cellular structure and function is considered by reference to histologic and exfoliative cytologic studies of the oral epithelia. Alcohol may influence the proliferative cells by both intracellular (e.g., endocytosis) and intercellular (permeability) pathways. The carcinogenic exposure of the proliferating stem cells in the basal layer may be regulated through these pathways. Individual variation might help explain why oral cancer arises in some people who smoke and consume excess alcohol, but not in most. Efforts to reduce this burden on the individual and society must be directed toward patient and professional education and research on genetic susceptibility. NIAAA Glossary Terms:  conference proceedings, cancer, AODR disorder, ethanol, AOD use, alcoholic beverage, tobacco in any form, risk factors, oral disorder, carcinogenesis, cell and cell structure, cell function, histologic study, endocytosis, membrane permeability, epithelium, stem cell, smoking, heavy AOD use, individual differences, genetic trait, genetic variance, prevention through education, literature review

Yokoyama A, and Omori T.  Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers (literature review).  Alcohol 35(3):175-185, April 2005.

(No abstract available.)

Philip J. Brooks and Jacob A. Theruvathu.  DNA adducts from acetaldehyde: Implications for alcohol-related carcinogenesis.  Alcohol 35(3):187-193, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines the role of deoxyribonucleic acid (DNA)-acetaldehyde adducts in alcohol-related carcinogenesis. Alcohol consumption is causally related to increased risk of cancer of the upper gastrointestinal tract, and the formation of acetaldehyde from ethanol metabolism seems to be the major underlying mechanism. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA-acetaldehyde adduct is N2-ethyl-2′-deoxyguanosine, which is increased in liver DNA from ethanol-treated rodents and in white blood cells from human alcohol abusers. However, evidence of its mutagenicity in mammalian cells is lacking. Another adduct, 1,N2-propano-2′-deoxyguanosine (PdG), which is formed from acetaldehyde in the presence of histones and other basic molecules, has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. This adduct can exist either as a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in PdG repair and its secondary adducts may contribute to susceptibility to alcohol-related carcinogenesis. NIAAA Glossary Terms:  conference proceedings, cancer, AODR disorder, carcinogenesis, adduct, DNA, proteins, acetaldehyde, ethanol metabolism, mutation, animal study, human study, laboratory rat, laboratory mice, deoxyribonucleosides, individual differences, genetic variance, biochemical mechanism, literature review

Iain H. McKillop and Laura W. Schrum.  Alcohol and liver cancer.  Alcohol 35(3):195-203, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines alcohol consumption as a risk factor for liver cancer. Hepatocellular carcinoma, the eighth most frequent cancer in the world, accounts for approximately 500,000 deaths a year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly in association with known risk factors, with cirrhosis being the most common precursor to its development. The liver is the major site of ethanol metabolism, in which alcohol dehydrogenase catalyzes the formation of acetaldehyde and free radicals. These bind rapidly to numerous cellular targets, including components of cell signaling pathways and deoxyribonucleic acid (DNA). In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic alcohol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde, resulting in further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants, including S-adenosyl-L-methionine and plant-derived flavonoids, as therapeutic agents. NIAAA Glossary Terms:  conference proceedings, cancer, liver disorder, AODR disorder, ethanol, carcinoma, hepatocyte, risk factors, liver cirrhosis, ethanol metabolism, alcohol dehydrogenases, acetaldehyde, free radicals, cell signaling, DNA, oxidative stress, glutathione, antioxidants, detoxification, chronic AODE, inducible enzymes, cytochrome P450 2E1, S-adenosylmethionine, flavonoids, drug therapy, literature review

Vay Liang W. Go, Anna Gukovskaya, and Stephen J. Pandol.  Alcohol and pancreatic cancer.  Alcohol 35(3):205-211, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines alcohol consumption as a risk factor for pancreatic cancer. Heavy alcohol consumption is known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, leading to fibrosis; (5) mutation of genes for enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco on metabolism of NNK (a tobacco-specific nitrosamine carcinogen); and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process toward the development of pancreatic cancer. NIAAA Glossary Terms:  conference proceedings, pancreatic disorder, cancer, AODR disorder, AOD consumption, heavy AOD use, chronic pancreatitis, endocrine pancreas, exocrine pancreas, inflammation, carcinogenesis, ethanol metabolism, acetaldehyde, fatty acid ethyl esters, enzymes, gene transcription, nuclear factor-kappa B, biological activation, oxygen radicals, antioxidants, pancreatic stellate cell, fibrosis, mutation, cytochrome P450, glutathione S-transferases, alcehyde dehydrogenases, trypsin, enzyme inhibitors, synergistic drug interaction, tobacco in any form, alcoholic beverage, nitrosamine, apoptosis, cell proliferation, risk factors, genetic variance, diet, environmental factors, lifestyle, acute AODE, chronic AODE, literature review

Ramona G. Dumitrescu and Peter G. Shields.  The etiology of alcohol-induced breast cancer.  Alcohol 35(3):213-225, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, discusses the etiology of alcohol-induced breast cancer. Most epidemiologic studies in women, as well as most experimental studies in animals, have shown that alcohol consumption is associated with increased breast cancer risk. Several possible mechanisms are examined. Alcohol-metabolizing enzymes are present in human breast tissue, and acetaldehyde, the first metabolic product of ethanol, is a known mutagen. Although acetaldehyde is only weakly mutagenic, results of some human studies implicate it in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species resulting from ethanol metabolism may be involved in breast carcinogenesis by causing damage, as well as by generating adducts with DNA and proteins. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. Alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some studies indicate that genetic variants of one-carbon metabolism genes might increase risk of alcohol-related breast cancer. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation. NIAAA Glossary Terms:  conference proceedings, cancer, breast, AODR disorder, risk factors, female, AOD consumption, ethanol metabolism, acetaldehyde, ethanol-to-acetaldehyde metabolism, mutagenesis, genetic trait, oxygen radicals, adduct, DNA, proteins, estrogens, receptors, folates, DNA metabolism, genetic polymorphism, biochemical mechanism, literature review

Shelly C. Lu and José M. Mato.  Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer.  Alcohol 35(3):227-234, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines the roles of essential enzyme methionine adenosyltransferase (MAT) and the principal methyl donor S-adenosylmethionine (SAMe) in the pathogenesis of alcohol-related liver cancer. The genes (MAT1A and MAT2A) encode for MAT, which catalyzes the biosynthesis of SAMe, is a precursor of glutathione in the liver. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This has pathogenic importance because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth. Rats fed ethanol intragastrically for 9 weeks also exhibit a relative switch in hepatic MAT expression, decreased SAMe levels, hypomethylation of c-myc oncogene, increased c-myc expression, and increased accumulation of DNA strand breaks. Patients with alcoholic liver disease have decreased hepatic MAT activity due to decreased MAT1A expression and inactivation of MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis. Consequences of chronic hepatic SAMe depletion have been examined in MAT1A knockout mice, which have increased susceptibility to liver injury; they develop spontaneous steatohepatitis by 8 months, and HCC by 18 months. There is growing evidence that, in addition to being a methyl donor, SAMe controls hepatocyte growth response and death response. Transient SAMe depletion is necessary for liver regeneration, but chronic hepatic SAMe depletion may lead to malignant transformation. Interestingly, SAMe is antiapoptotic in normal hepatocytes, but proapoptotic in liver cancer cells, which should make it useful for both chemoprevention and treatment of HCC. NIAAA Glossary Terms:  conference proceedings, alcoholic liver disorder, cancer, AODR disorder, S-adenosylmethionine, gene, gene expression, glutathione, carcinoma, hepatocyte, pathogenesis, intragastric administration, isoenzyme, oncogene, gene knockout technology, fatty liver, hepatitis, apoptosis, drug therapy, literature review

Joel B. Mason and Sang-Woon Choi.  Effects of alcohol on folate metabolism: Implications for carcinogenesis.  Alcohol 35(3):235-241, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines the carcinogenetic implications of ethanol's effects on folate metabolism. Epidemiological studies implicate excess ethanol ingestion as well as low dietary folate intake as risk factors for several cancers, and support the concept that these two factors act synergistically. The relation is biologically plausible because ethanol reduces the bioavailability of dietary folate and inhibits certaint folate-dependent biochemical reactions. For example, alcohol ingestion in animals is known to inhibit folate-mediated methionine synthesis. This may interrupt critical methylation processes mediated by S-adenosylmethionine, the activated form of methionine. Consistent with the observed inhibition of methionine synthesis is the observation that chronic alcohol ingestion in laboratory animals is known to produce hypomethylation of DNA in the colonic mucosa, a constant feature of early colorectal neoplasia. Inhibition of methionine synthase also creates a "methylfolate trap," analogous to what occurs in vitamin B12 deficiency. There is also some evidence that alcohol may redirect the utilization of folate toward serine synthesis, thereby interfering with a critical function of methylenetetrahydrofolate, namely thymidine synthesis. Although a mechanistic link between alcohol and impaired folate metabolism in carcinogenesis is still not definitively established, such a link should be pursued in future studies because of the intimate metabolic relation between alcohol and folate metabolism. NIAAA Glossary Terms:  conference proceedings, ethanol, folates, metabolism, AODR disorder, cancer, carcinogenesis, risk factors, synergistic drug interaction, bioavailability, biochemical mechanism, S-adenosylmethionine, methionine, chronic AODE, DNA metabolism, colon, intestinal mucosa, neoplasm, synthetases, vitamin B12, nutritional deficiency, literature review

Dennis R. Petersen.  Alcohol, iron-associated oxidative stress, and cancer.  Alcohol 35(3):243-249, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines the role of ethanol-induced iron accumulation, and consequent oxidative stress, in the pathogenesis of liver cancer. Oxidative stress plays an important role in the initiation and promotion events of carcinogenesis. Alcoholic liver disease is associated with significant oxidative stress as well as the hepatic accumulation of iron, a transition element that also initiates oxidative stress. The combined prooxidant potentials of ethanol and iron are at least additive and may be synergistic in the induction of hepatocellular oxidative stress and antioxidant depletion. One cellular consequence of sustained oxidative stress and redox imbalance resulting from the combined actions of alcohol and iron is lipid peroxidation, resulting in the production of aldehydic products such as 4-hydroxy-2-nonenal, which has been linked to site-specific mutations of the p53 gene. In addition, the accumulation of iron in hepatic macrophages isolated from laboratory animals chronically ingesting alcohol is associated with activation of nuclear factor-kappa B and production of tumor necrosis factor-alpha, providing a proinflammatory cellular environment also favorable for initiation and promotion of carcinogenesis. Consequently, there is persuasive evidence that the potential of ethanol and iron to induce oxidative stress may be an important pathogenic mechanism for the increased occurrence of hepatocellular carcinoma in individuals with hepatic iron overload who ingest alcohol. NIAAA Glossary Terms:  conference proceedings, cancer, carcinoma, liver, AODR disorder, carcinogenesis, iron metabolism disorder, oxidative stress, synergistic drug interaction, hepatocyte, antioxidants, peroxidation, lipids, oxidation-reduction, mutation,  biogenic aldehyde, aldehydes, macrophage, nuclear factor-kappa B, tumor necrosis factor-alpha, inflammation, pathogenesis, literature review

Xiang-Dong Wang.  Alcohol, vitamin A, and cancer.  Alcohol 35(3):251-258, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines the role of alcohol-associated vitamin A deficiency in the etiology of cancer. Chronic and excessive alcohol intake is associated with increased risk of a variety of cancers. Retinoids (vitamin A and its derivatives) exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels in alcoholics are well documented. Research on the mechanisms by which excessive alcohol interferes with retinoid metabolism shows that (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid, which is catalyzed by alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP 2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. Consequently, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active vitamin A derivative and a ligand for both retinoic acid receptors and retinoid X receptors. Alcohol-impaired retinoic acid homeostasis also interferes with retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and retinoic acid "cross-talk" with the mitogen-activated protein kinase (MAPK) signaling pathway. Retinoic acid supplementation restores the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. Use of retinoids for prevention of alcohol-related carcinogenesis in humans will require improved understanding of the alcohol-retinoid interaction and the molecular mechanisms involved, particularly the detrimental effects of polar metabolites of vitamin A. NIAAA Glossary Terms:  conference proceedings, cancer, etiology, AODR disorder, heavy AOD use, chronic AODE, vitamin A deficiency, retinoids, retinoic acid, cell proliferation,  cell growth and differentiation, apoptosis, alcohol dehydrogenases, cytochrome P450, cytochrome P450 2E1, inducible enzymes, enzyme induction, ligand, receptors, homeostasis, cell signaling, gene expression, mitogens, protein kinases, literature review

Vivian Y. Shin and Chi-Hin Cho.  Nicotine and gastric cancer.  Alcohol 35(3):259-264, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, examines nicotine as a risk factor for gastric cancer. About 60 cigarette smoke components are considered to be carcinogens, namely polycyclic aromatic hydrocarbons, nitrosamines, aromatic amine, trace metals, as well as nicotine. One of the active components in cigarette smoke is nicotine, which has an ambiguous association with tumorigenesis. Nonsteroidal antiinflammatory drugs are widely used as antitumor agents to treat patients with cancer by inhibiting cyclooxygenase-2 activity. Stimulation of tumor growth by nicotine involves different processes of cell proliferation and angiogenesis. Results from studies using animal xenograft models and cell cultures show that nicotine stimulates tumor growth through a cyclooxygenase-2–dependent pathway. Based on these findings, nicotine seems to be a potent mitogenic agent in modulating tumor cell proliferation, and selective cyclooxygenase-2 inhibitors are promising antitumor agents for gastric cancer in smokers. NIAAA Glossary Terms:  conference proceedings, nicotine, gastric disorder, cancer, carcinogenesis, smoking, cigarette, carcinogens, polycyclic hydrocarbons, nitrosamine, amines, aromatic hydrocarbons, inflammation, drug therapy, cyclooxygenase inhibitors, cell proliferation, angiogenesis, mitogens, enzyme inhibitors, literature review

Mia Hashibe, Kurt Straif, Donald P. Tashkin, Hal Morgenstern, Sander Greenland, and Zuo-Feng Zhang.  Epidemiologic review of marijuana use and cancer risk.  Alcohol 35(3):265-275, April 2005.

Summary: This paper, presented at a symposium on Mechanisms of Alcohol-Associated Cancers, held at Bethesda, Maryland in October 2004, reviews the epidemiology of cancer risk associated with marijuana use. Although young adults consider marijuana to be the least risky illicit drug, marijuana smoke contains several of the same carcinogens and co-carcinogens as tobacco tar, raising concerns that marijuana smoking may be a risk factor for tobacco-related cancers. The authors reviewed two cohort studies and 14 case-control studies with assessment of the association of marijuana use and cancer risk. Increased risks of lung or colorectal cancer due to marijuana smoking were not observed in the cohort studies. However, increased risks of prostate and cervical cancers among non-tobacco smokers, as well as adult-onset glioma among tobacco and non-tobacco smokers, were observed. The 14 case-control studies included 4 studies on head and neck cancers, 2 on lung cancer, 2 on non-Hodgkin's lymphoma, 1on anal cancer, 1 on penile cancer, and 4 on childhood cancers with assessment of parental exposures. Zhang et al. reported that marijuana use may increase risk of head and neck cancers in a hospital-based case-control study, with dose-response relations for both frequency and duration of use. However, Rosenblatt et al. reported no association between oral cancer and marijuana use in a population-based case-control study. An eightfold increase in lung cancer risk among marijuana users was observed in a lstudy in Tunisia, but there was no dose-response assessment, and marijuana may have been mixed with tobacco. Parental marijuana use during gestation was associated with increased risks of childhood leukemia, astrocytoma, and rhabdomyosarcoma, but dose-response relations were not assessed. In summary, not enough studies are available for adequate evaluation of marijuana impact on cancer risk. Several limitations of previous studies include possible underreporting where marijuana use is illegal, small sample sizes, and too few heavy marijuana users in the study sample. It is recommended that future studies focus on tobacco-related cancer sites; obtain detailed marijuana exposure assessment including frequency, duration, and amount of personal use as well as mode of use (cigarette, pipe, bong, or taken orally); adjust for tobacco smoking and conduct analyses on nonusers of tobacco; and use larger samples, meta-analyses, or pooled analyses to maximize statistical precision and investigate sources of differences in results. NIAAA Glossary Terms:  conference proceedings, marijuana in any form, cancer, carcinogens, carcinogenesis, AODR disorder, smoking, risk factors, risk analysis, lung disorder, head, neck, male genitals, case-control study, dose-response relationship, AOD use frequency, AOD use duration, AOD use pattern, parental AOD use, illicit drug, sample selection problems, meta-analysis, research issue, literature review

Jian-Ching Ren, Ali Banan, Ali Keshavarzian, Qianlong Zhu, Nancy LaPaglia, John McNulty, Nicholas V. Emanuele, and Mary Ann Emanuele.  Exposure to ethanol induces oxidative damage in the pituitary gland.  Alcohol 35(2):91-101, February 2005.

Summary: Chronic exposure of pubertal male rats to ethanol results in decreased serum testosterone and decreased or inappropriately normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, suggesting a functional defect in the pituitary. Animal studies support a role for ethanol-induced oxidative damage in the pathophysiology, but evidence in the pituitary is limited. This study examined markers of oxidative damage to lipids and proteins in pituitaries from rats consuming ethanol for 5, 10, 20, 30, and 60 days as well as markers of damage to nucleic acids in pituitaries after 60 days of ethanol consumption. There were increases in 8-oxo-deoxyguanosine immunoreactivity, a marker of oxidative damage to nucleic acids, and an overall increase in the lipid peroxidation markers malondialdehyde and 4-hydroxynonenal. Markers of protein oxidation (protein carbonylation and protein nitrotyrosination), were significantly increased after 30 and 60 days of ethanol consumption respectively. After 60 days of ethanol exposure, tranferase dUTP nick end labeling (TUNEL) assay revealed that cell death in the ethanol-treated pituitaries was not significantly different from that in the pair-fed controls at the time of examination. Serum testosterone, FSH, and LH were also measured after ethanol consumption for 5, 10, 20, 30, and 60 days. Testosterone levels were consistently lower through 5 to 60 days of ethanol exposure, whereas LH and FSH were inappropriately unchanged, suggesting pituitary malfunction. The results provide evidence for ethanol-induced oxidative damage to the pituitary, which may contribute to pituitary dysfunction. NIAAA Glossary Terms:  ethanol, testosterone, luteinizing hormone, follicle-stimulating hormone, chronic AODE, pituitary, oxidative stress, lipids, proteins, nucleic acids, peroxidation, malondialdehyde, biochemical markers, immunoassay, controlled study, comparative study, laboratory rat, animal study

Jian-Ching Ren, Qianlong Zhu, Nancy LaPaglia, Nicholas V. Emanuele, and Mary Ann Emanuele.  Ethanol-induced alterations in Rab proteins: Possible implications for pituitary dysfunction.  Alcohol 35(2):103-112, February 2005.

Summary: Pubertal male rats exposed chronically to ethanol have decreased serum testosterone; increased gonadotropins, pituitary luteinizing hormone (LH), and follicle stimulating hormone (FSH) content; and decreased or inappropriately normal serum LH and FSH levels, suggesting impaired secretion of gonadotropins. The molecular mechanisms remain undefined, but disruption of vesicle-mediated secretory processes is possible because intracellular protein trafficking pathways are involved in secretion of glycoproteins such as FSH and LH. Because small guanosine triphosphate (GTP)-binding proteins of Rab family have been implicated as key regulators of membrane and protein trafficking in mammalian cells, this study examined whether ethanol-impaired pituitary FSH and LH secretion is associated with changes in Rab proteins, particularly Rab1B, Rab3B, Rab6, and Rab11. Male laboratory rats 35 days old were pair-fed a Lieber–DeCarli diet with ethanol or without ethanol for 5 to 60 days. Serum testosterone levels were decreased after ethanol exposure, while LH and FSH were inappropriately unchanged. Immunohistochemical staining showed decreased Rab1B, Rab3B, and Rab11 protein levels in ethanol-treated pituitaries. Immunoblotting showed that ethanol induced a transient reduction in Rab6 after 5 days of ethanol exposure, whereas Rab3B decreased after 20 days, Rab11 after 30 days, and Rab1B after 60 days. Despite these changes in Rab proteins, messenger ribonucleic acid (mRNA) levels were unaffected by ethanol exposure. Thus reductions in key Rab proteins may lead to altered vesicle trafficking and may play a role in disruption of pituitary FSH and LH secretion caused by ethanol. NIAAA Glossary Terms:  ethanol, testosterone, luteinizing hormone, follicle-stimulating hormone, chronic AODE, pituitary, glycoproteins, GTP-binding protein, laboratory rat, controlled study, comparative study, mRNA, immunoassay, animal study

Mariann R. Piano, Timothy M. Carrigan, and Dorie W. Schwertz.  Sex differences in ethanol liquid diet consumption in Sprague-Dawley rats.  Alcohol 35(2):113-118, February 2005.

Summary: Sex differences in ethanol consumption between different strains of male and female rats have been reported, but these differences have not been studied in rats of the Sprague-Dawley strain. This study therefore examined body growth, ethanol consumption (ml/day and g/kg/day, and blood ethanol levels (BELs) in adult male and female (n = 6–8 per group; sham-operated and ovariectomized) Sprague-Dawley rats consuming different concentrations (3% to 9% v/v) of the Lieber-DeCarli liquid ethanol diet. Throughout the study, male rats weighed significantly more than both female groups, and ovariectomized female rats weighed more than sham female rats. Ethanol diet consumption (ml/day) was significantly greater in males than in females at higher ethanol concentrations, but when the diet consumption was expressed in grams of ethanol/kg/day, the sham-operated female group was shown to consume significantly more ethanol than the male group. Even though there were differences in ethanol intake, blood ethanol levels were similar among the groups. The data indicate that, like other strains, Sprague-Dawley rats exhibit sex differences in their pattern of body growth (weight gain) and ethanol intake, but blood ethanol levels were similar among the groups. NIAAA Glossary Terms:  ethanol, AOD consumption, gender differences, animal strains, laboratory rat, BAC, controlled study, comparative study, ovary, operative surgery, body weight, animal study

Wendy N. Strother, William J. McBrideabc, Lawrence Lumeng, and Ting-Kai Li.  Effects of acute administration of ethanol on cerebral glucose utilization in adult alcohol-preferring and alcohol-nonpreferring rats,  Alcohol 35(2):119-128, February 2005.

Summary: The [14C]-2-deoxyglucose (2-DG) technique was used to examine local cerebral glucose utilization (LCGU) rates after acute ethanol administration in selected brain regions of alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. Adult male P and NP rats were injected intraperitoneally with saline, 0.25 g/kg, or 1.0 g/kg ethanol 10 minutes before an intravenous bolus of [14C]2-DG (125 μCi/kg). Timed arterial blood samples were collected over 45 minutes and assayed for plasma glucose, ethanol, and [14C]2-DG levels. Image densities were determined by quantitative autoradiography and LCGU values calculated. Data were collected from several key limbic, basal ganglionic, cortical, and subcortical structures. Low-dose ethanol (0.25 g/kg) significantly decreased LCGU rates in several brain regions including the medial prefrontal cortex, olfactory tubercles, and the CA1 subregion of the hippocampus of P rats but had no significant effects on LCGU rates in the NP rats. Moderate-dose ethanol (1.0 g/kg) also significantly lowered LCGU rates in many brain regions of P rats, including key limbic structures, such as the medial prefrontal cortex, olfactory tubercles, ventral tegmental area, basolateral nucleus of the amygdala, lateral septum, and ventral pallidum. Moderate-dose ethanol also significantly lowered LCGU rates in the medial prefrontal cortex as well as in the habenula of NP rats. All other regions were unaffected in the NP rats. The results support the suggestion that certain central nervous system regions of P rats may be more sensitive than those of NP rats to the effects of low to intermediate doses of ethanol. NIAAA Glossary Terms:  ethanol, AOD consumption, animal selectively bred for alcohol preference, laboratory rat, controlled study, comparative study, central nervous system, cerebrum, glucose metabolism, cerebral cortex, limbic system,  basal ganglia, prefrontal cortex, olfactory system, hippocampus, ventral tegmental area, amygdala, radioactive chemical elements, carbon, animal model, animal study

Helen J.K. Sable, Zachary A. Rodd, Richard L. Bell, Jonathan A. Schultz, Larry Lumeng, and William J. McBride.  Effects of ethanol drinking on central nervous system functional activity of alcohol-preferring rats.  Alcohol 35(2):129-135, February 2005.

Summary: The [14C]-2-deoxyglucose (2-DG) technique was used to assess the rates of local cerebral glucose utilization (LCGU) in key limbic, cerebral cortical, hippocampal, basal ganglionic, and subcortical regions of alcohol-preferring (P) rats following chronic 24-hour free-choice ethanol drinking. Adult male P rats were submitted to either 8 continuous weeks of two-bottle access to 15% ethanol and water (E-C group); 8 weeks of identical two-bottle access followed by 2 weeks of ethanol deprivation (E-D group); cycles of 2 weeks of two-bottle ethanol access and 2 weeks of deprivation, repeated for four cycles (E-RD group); or water only treatment (ethanol-naive [E-N] group). A single pulse of [14C]-2-DG (125 μCi/kg) was administered through a venous catheter, and timed arterial blood samples were collected over 45 minutes and later assayed for plasma glucose and [14C]-2-DG concentrations. Quantitative autoradiography was used to determine 14C densities, and LCGU values were calculated. Except for a few small differences in the hippocampus, no significant differences were found in any of the central nervous system (CNS) regions examined among the four experimental groups of P rats. Animals in the E-D group had lower LCGU rates in the anterior hippocampal CA1 subregion than animals in the E-N, E-C, and E-RD groups. In the anterior hippocampal CA3 subregion and the anterior hippocampal dentate gyrus, the E-D group had significantly lower LCGU rates than the E-RD group. Overall, the results of this study indicate that 24-hour ethanol-drinking has little effect on CNS functional neuronal activity in P rats. NIAAA Glossary Terms:  ethanol, AOD consumption, animal selectively bred for alcohol preference, laboratory rat, animal model, glucose metabolism, central nervous system, limbic system, cerebral cortex, hippocampus, basal ganglia, radioactive chemical elements, radiography, carbon, controlled study, comparative study, animal study

Julie Broadbent, Kathryn M. Kampmueller, and Sharon A. Koonse.  Role of dopamine in behavioral sensitization to ethanol in DBA/2J mice.  Alcohol 35(2):137-148, February 2005.

Summary: It has been proposed that behavioral sensitization plays an important role in addiction. Elucidation of the neural processes mediating sensitization may therefore lead to the development of new pharmacotherapeutic treatments. Numerous studies have examined sensitization to psychostimulants and morphine, but despite the prevalence of alcoholism the neural processes underlying sensitization to ethanol have not been identified. This study examined the role of different components of the dopamine system in sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Sensitization was induced by administering ethanol (2 g/kg) intraperitoneally before locomotor activity trials. Control groups received saline (12.5 ml/kg) intraperitoneally before each activity trial. The ability of the dopamine uptake inhibitors GBR 12909 (3.33–10.0 mg/kg) and bupropion (20 and 30 mg/kg) to cross-sensitize to ethanol was then examined. In addition, the effects of the dopamine D1 receptor agonist SKF 82958 (0.1–1.0 mg/kg), the dopamine D2/D3 agonist quinpirole (0.05 and 0.1 mg/kg), and a combination of SKF 82958 and quinpirole were examined. Cross-sensitization was observed between the dopamine uptake inhibitor GBR 12909 and ethanol, but bupropion, a less selective uptake inhibitor, did not exhibit cross-sensitization. Similarly, stimulation of D1 and D2/D3 receptors did not cause cross-sensitization even when the agonists were administered together. Collectively, these data suggest that sensitization to ethanol is associated with changes in the dopaminergic system. NIAAA Glossary Terms:  ethanol, AOD sensitivity, addiction, AOD dependence, intraperitoneal administration, dopamine, dopaminergic neuron, locomotion, controlled study, comparative study, laboratory mice, neurotransmitter uptake inhibitors, agonists, animal study

C.R. Goodlet.  Transitions, aims, and initiatives for Alcohol with the new editorship (Editorial).  Alcohol 35(1):1-2, January 2005.

(No abstract available.)

David M. Umulis, Nihat M. Gürmen, Prashant Singh, and H. Scott Fogler.  A physiologically based model for ethanol and acetaldehyde metabolism in human beings.  Alcohol 35(1):3-12, January 2005.

Summary: Pharmacokinetic models for ethanol metabolism have contributed to understanding ethanol clearance in human beings, but they fail to account for ethanol's metabolite, acetaldehyde. Acetaldehyde accumulation leads to toxic signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Because determining the levels of acetaldehyde in blood or other tissues is difficult due to artifactual formation and other technical issues, the authors developed a physiologically based pharmacokinetic (PBPK) model that is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. Average enzymatic rate laws were derived for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), kinetic parameters were determined from the literature, and best-fit parameters were found by minimizing the squared error between the profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. The model also shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels about one-tenth of what they would be if the reaction were irreversible. NIAAA Glossary Terms:  ethanol metabolism, acetaldehyde, pharmacokinetics, scientific model, stomach, gastrointestinal tract, liver, body fluid, muscle, enzymes, alcohol dehydrogenases, aldehyde dehydrogenases, aldehyde dehydrogenase isoenzyme, correlation analysis, biochemical reaction property, theoretical study

Blair U. Bradford and Ivan Rusyn.  Swift increase in alcohol metabolism (SIAM): Understanding the phenomenon of hypermetabolism in liver (Review).  Alcohol 35(1):13-17, January 2005.

Summary: Continuous exposure to ethanol is known to produce adaptive changes in liver alcohol and oxygen metabolism. A considerable burst of hepatic respiration can also occur after administration of a single large dose of ethanol and results in a near doubling of ethanol metabolism, high demand for oxygen, and downstream or pericentral hypoxia. The phenomenon is called the swift increase in alcohol metabolism (SIAM).These dramatic changes in rates of ethanol metabolism and tissue concentrations of oxygen are not due to induced enzyme activity in liver. They depend on activation of mitochondrial function, increased co-factor supply for nicotinamide adenine dinucleotide (NAD)-dependent alcohol metabolism, depletion of glycogen reserves, liberation of fatty acids through activation of an adrenergic response to ethanol providing substrate for catalase, and activation of Kupffer cells, the hepatic macrophages responsible for production of cytokines and prostaglandins. Understanding the mechanisms of hypermetabolism in liver can have vital ramifications for knowledge of both alcohol-related and alcohol-unrelated liver damage because hypoxia resulting from hypermetabolism can compound effects of pharmaceuticals and environmental agents on the liver. SIAM is an excellent example of the complexity of cell-cell interactions in liver and extrahepatic regulation of biochemical and molecular events in this organ. The authors anticipate consideration of this important phenomenon in studies of liver disease and biochemistry. NIAAA Glossary Terms:  ethanol metabolism, oxygen, hypoxia, mitochondria, NAD, glycogen, fatty acids, epinephrine, catalase, Kupffer cell, macrophage, cytokines, prostaglandins, AODR disorder, liver disorder, alcoholic liver disorder, drug therapy, environmental factors, biochemical mechanism, literature review

George Fein and Bennett Landman.  Treated and treatment-naive alcoholics come from different populations.  Alcohol 35(1):19-26, January 2005.

Summary: The presumption that associations found in studies of select samples of alcoholic apply to all alcoholics (including untreated alcoholics in the general population) is an example of Berkson's fallacy (defined as a spurious correlation between two diseases or between a disease and a risk factor arising from biased sampling). This study examined whether treated and untreated alcoholics have similar early alcohol use histories by comparing abstinent alcoholics (treated and sober at least 6 months) with treatment-naive alcoholics (active drinkers). The participants were 14 pairs of women and 25 pairs of men matched on the age at which they first met criteria for heavy alcohol use (80 drinks/month for women, 100 drinks/month for men). Retrospective alcohol use information was obtained by the timeline follow-back interview method. Alcohol dose and duration of use were subsequently computed for two intervals: (1) time between the first drink and the date at which the person met criteria for heavy drinking and (2) time between meeting criteria for heavy drinking and current age of the treatment-naive person from each pair. Alcohol dose did not differ between the two groups during the period before the matching “heavy drinking” criteria were met. After heavy alcohol use criteria were met, the treated alcoholics had higher average and peak alcohol doses than the treatment-naive alcoholics. This led to rejection of the hypothesis that the treatment-naive alcoholics and the treated alcoholics have similar alcohol use trajectories over time, with the treatment-naive sample simply being observed earlier in its alcohol use histories. The authors concluded instead that the two groups come from different alcohol-using populations. In fact, the treated alcoholics had alcohol doses more than 50% higher than those of treatment-naive alcoholics in the years just after they began drinking heavily. This finding supports the suggestion that results from studies of alcoholics in treatment or after treatment (i.e., most studies of alcoholics) cannot be generalized to untreated individuals (i.e., the majority of alcoholics. NIAAA Glossary Terms:  AOD dependence, AOD use pattern, heavy AOD use, AOD intake per occasion, treatment factors, treatment outcome, help-seeking behavior, hypothesis testing,  sampling bias, interview, retrospective study, patient AODU history, comparative study, human study

Giancarlo Colombo, Carla Lobina, Paola Maccioni, M. Francesca Mascia, Alessandro Orrù, Gian Luigi Gessa, and Mauro A.M. Carai.  Suppression of acquisition of alcohol-drinking behavior by the concurrent availability of saccharin in Sardinian alcohol-preferring (sP) rats.  Alcohol 35(1):27-33, January 2005.

Summary: The effect of concurrent presentation of saccharin on the acquisition of alcohol-drinking behavior was investigated in selectively bred Sardinian alcohol-preferring (sP) rats. Alcohol-naive rats were given access to saccharin (0%, 0.01%, 0.1%, 1%, or 3% w/v in water), alcohol (10% v/v in water), and water under the home cage, three-bottle, free-choice regimen, with unlimited access for 24 hours/day for 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, reaching polydipsic-like values at the 0.1% concentration. In contrast, alcohol intake was a U function of saccharin concentration, being virtually suppressed in the groups of rats exposed to the highly accepted 0.1% and 1% concentrations of saccharin. The results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin suppresses acquisition of alcohol-drinking behavior in sP rats and (2) the suppressive effect of saccharin solutions on the acquisition of alcohol-drinking behavior in sP rats was positively related to their degree of acceptability. The authors hypothesize that immediate and continuous access to the highly palatable saccharin solution may have distracted the rat, preventing it from consuming the amounts of alcohol solution needed to disclose and experience the psychopharmacologic effects of alcohol on which alcohol-drinking behavior in sP rats is based. NIAAA Glossary Terms:  saccharin, ethanol, AOD use behavior, animal selectively bred for AOD preference, laboratory rat, dose-response relationship, animal study

Giancarlo Colombo, Carla Lobina, Paola Maccioni, M. Francesca Mascia, Alessandro Orrù, Gian Luigi Gessa, and Mauro A.M. Carai.  Suppression of maintenance of alcohol-drinking behavior by the concurrent availability of saccharin in Sardinian alcohol-preferring (sP) rats.  Alcohol 35(1):35-41, January 2005.

Summary: This study investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol (10% v/v in water) and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 hours/day for 8 consecutive weeks. Next, a third bottle, containing saccharin (0%, 0.01%, 0.1%, 1%, or 3% w/v in water), was concomitantly offered for an additional 10 consecutive days. Saccharin solution intake was an inverted-U function of saccharin concentration, with the 0.1% saccharin solution having the highest acceptance. Alcohol intake was a U-shaped function of saccharin concentration, being reduced by 65%–95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. The authors hypothesize that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent. NIAAA Glossary Terms:  saccharin, ethanol, AOD use behavior, animal selectively bred for AOD preference, laboratory rat, dose-response relationship, animal study

Arthur Tomie, Jennifer Gittleman, Erik Dranoff, and Larissa A. Pohorecky.  Social interaction opportunity and intermittent presentations of ethanol sipper tube induce ethanol drinking in rats.  Alcohol 35(1):43-55, January 2005.

Summary: The effects of social interaction opportunity (SIO) and intermittent presentations of the ethanol sipper tube (IS) on autoshaping of ethanol drinking were evaluated in nondeprived rats. Rats were assigned to one of seven groups. Two groups experienced brief IS presentation, either paired with or randomly related to the response-independent raising of a guillotine door (D) revealing the presence of a conspecific male rat in a holding cage (SIO). Two control groups received similar training except that the D revealed an empty cage, whereas a third control group received IS but neither D nor SIO. For two additional control groups, the ethanol sipper tube was continuously available during the session, with and without SIO, with both groups receiving intermittent D. In IS conditions, procedures with SIO induced more ethanol intake than non-SIO procedures did, indicating that SIO contributed to ethanol intake, but D procedures did not differ from non-D procedures, indicating that ethanol drinking was not related to the operation of the door. Groups that received training procedures providing for both SIO and IS showed more rapid initiation of ethanol intake and more rapid escalation of ethanol intake as the concentration of ethanol in the sipper tube conditioned stimulus was increased across sessions. Theoretical explanations based on cue at response manipulandum/autoshaping, schedule-induced polydipsia, incentive sensitization, and intermittency-induced arousal are considered. NIAAA Glossary Terms:  animal behavior, social behavior, ethanol, laboratory rat, controlled study, AOD intake per occasion, AOD use behavior, cue reactivity, animal study

Rukhsana Sultana, Bhupanapadu Sunkesula Solomon Raju, Varsha Sharma, Pallu Reddanna, and Phanithi Prakash Babu.  Formation of acetaldehyde adducts of glutathione S-transferase A3 in the liver of rats administered alcohol chronically.  Alcohol 35(1):57-66, January 2005.

Summary: Hepatic tissue damage induced by chronic ethanol exposure is mediated through acetaldehyde and associated with reactive oxygen species, which impair cellular defense mechanisms. Because glutathione S-transferases (GSTs) play an important role in the detoxification of xenobiotics and reactive oxygen species, this study tested the effect of ethanol administration on structural and functional characteristics of rat liver Alpha class GSTs (rGSTs). Western blot analysis revealed an appreciable change in the expression of rGSTA3 subunit levels, whereas no change was observed in activity after chronic alcohol treatment. Reverse-phase high performance liquid chromatographic analysis of rGSTs that were affinity purified with glutathione showed a 1.07-fold increase in rGSTA3 subunit levels in rats chronically treated with ethanol. In addition, liquid chromatographic-electrospray ionization mass spectrometric analysis of GSTs that were affinity purified with glutathione showed the formation of acetaldehyde adducts to the rGSTA3 subunit. Given the abundant expression of rGSTA3 subunit and acetaldehyde adduct formation, these results support the suggestion that modification of rGSTA3 subunit, thus impairing its function, in alcohol-exposed rats may contribute to the progression of alcohol-induced liver damage. NIAAA Glossary Terms:  alcoholic liver disorder, ethanol, acetaldehyde, oxygen radicals, free radicals, oxidative stress, glutathione S-transferases, xenobiotics, detoxification, Western blotting, gene expression, chronic AODE, high pressure liquid chromatography, adduct, spectrometry, disease course, laboratory rat, animal study

Cynthia A. Dlugos.  Analyses of smooth endoplasmic reticulum of cerebellar parallel fibers in aging, ethanol-fed rats.  Alcohol 35(1):67-73, January 2005.

Summary: The smooth endoplasmic reticulum (SER), a calcium storage organelle, is essential for normal neuronal function. Dilation of the SER is pathologic, a threat to neuronal calcium homeostasis, and has been reported within the dendrites of cerebellar Purkinje neurons of aging rats after lengthy ethanol treatment. This study investigated ethanol-related alterations of parallel fiber SER, which have not been studied despite the fact that such dilation may precede and contribute transsynaptically to SER dilation and degeneration in Purkinje neuron dendrites. Male Fischer 344 rats (N = 120; 12 months old) were randomly divided into three dietary groups (40 rats per group) and fed rat chow, the AIN-93M liquid control diet, or the AIN-93M liquid ethanol diet (without water) for 5, 10, 20, or 40 weeks (30 rats per time point). Sections from posterior vermal lobules were viewed with electron microscopy, and maximum and minimum diameters of parallel fiber SER profiles were measured. Ethanol-related dilation of parallel fiber SER was not found after 5, 10, 20, or 40 weeks of treatment, but age-related dilation of parallel fiber SER profiles did occur. The results support the suggestions that (1) parallel fiber SER, unlike the SER in Purkinje neurons, is insensitive to ethanol and (2) the mechanisms by which ethanol and aging alter cerebellar function and structure are different. NIAAA Glossary Terms:  endoplasmic reticulum, ethanol, chronic AODE, calcium metabolism disorder, homeostasis, neurotransmission, neuron, Purkinje cell, dendrite, cerebellum, laboratory rat, controlled study, age differences, animal study

Judit Garriga, Joaquim Fernández-Solá, Ester Adanero, Alvaro Urbano-Márquez, and Roser Cussó.  Metabolic effects of ethanol on primary cell cultures of rat skeletal muscle.  Alcohol 35(1):75-82, January 2005.

Summary: Glycogen accumulates in the skeletal muscles of individuals who have consumed ethanol chronically. Changes in the energy balance caused by ethanol consumption might lead to alcoholic myopathy. Experimental models used in the past, such as skeletal muscle biopsy samples of alcohol-dependent individuals or animals, do not distinguish between direct and indirect effects of ethanol (i.e., alterations to the nervous or endocrine system). This study evaluated the direct effect of ethanol on skeletal muscle glycogen concentrations and related glycolytic pathways. Changes in metabolite concentrations and enzyme activities of carbohydrate metabolism were measured in primary cell cultures of rat skeletal muscle exposed to ethanol for two periods. The concentrations of glycolytic metabolites and the activities of several enzymes that regulate glucose and glycogen metabolism were measured. After a short exposure to ethanol (6 hours), glucose metabolism slowed. Glycogen accumulation was observed after 48 hours of ethanol exposure. NIAAA Glossary Terms:  chronic AODE, ethanol, glycogen, skeletal muscle, AODR myopathy, nervous system, endocrine system, glycolysis, carbohydrate metabolism disorder, enzymes, glucose, cell culture study, laboratory rat, animal study

T.R. Jerrells.  Change of Editor-in-Chief for Alcohol (Editorial).  Alcohol 34(2):99-100, October 2004.

(No abstract available.)

John J. Woodward.  Fyn kinase does not reduce ethanol inhibition of zinc-insensitive NR2A-containing N-methyl-D-aspartate receptors.  Alcohol 34(2):101-105, October 2004.

Summary: Ethanol inhibits ion flux through N-methyl-D-aspartate (NMDA) receptors at concentrations that are associated with intoxicated behavior. NMDA receptor sensitivity to ethanol is influenced by subunit composition and interactions with cytoskeletal elements. Evidence supports the suggestion that the inhibitory effect of ethanol on NMDA receptors containing the NR1/2A subunit is reduced by tyrosine phosphorylation catalyzed by Fyn kinase. However, tyrosine kinases also reduce the high-affinity zinc sensitivity of NR1/2A receptors, suggesting that kinase-dependent effects on ethanol inhibition may be secondary to relief of zinc inhibition. The present study determined the effect of Fyn kinase on the ethanol inhibition of NR1/2A receptors under conditions in which zinc sensitivity is eliminated. Human embryonic kidney 293 (HEK 293) cells were transiently transfected with wild-type or mutant NMDA subunits, and glutamate-activated currents were measured using patch-clamp electrophysiology. Inclusion of a tyrosine phosphatase inhibitor in the recording pipette eliminated the potentiation of NR1/2A currents by heavy metal chelators. Under these conditions, Fyn kinase did not reduce ethanol inhibition of wild-type receptors and also had no effect on the magnitude of ethanol inhibition of zinc-insensitive NR1/2A(H128S) receptors. These results indicate that Fyn kinase does not directly affect the ethanol sensitivity of NR1/2A receptors. NIAAA Glossary Terms:  NMDA receptors, ethanol, ion, AOD intoxication, AODR behavioral problem, cytoskeleton, tyrosine, phosphorylation, tyrosine kinase, zinc, mutation, enzyme inhibitors, structure activity relationship, cell culture study, human study

Maria Cristina Caroleo, Nicola Costa, Paola Tirassa, and Luigi Aloe.  Nerve growth factor produced by activated human monocytes/macrophages is severely affected by ethanol.  Alcohol 34(2):107-114, October 2004.

Summary: Although the precise cellular target of ethanol's impairment of immune response remains unknown, several studies have shown that ethanol acts primarily by interfering with the ability of blood monocyte-derived macrophages to produce cytokines and growth factors. This study tested the hypothesis that exposure to ethanol would affect the synthesis of nerve growth factor (NGF) as well as expression of NGF receptor trkA in monocytes/macrophages, because NGF is known to play a key role in responses mediated by this cell population. Because NGF has been reported to affect the synthesis of proinflammatory cytokines, the study also evaluated whether the production of tumor necrosis factor-alpha (TNF-α) would be affected by ethanol-mediated changes in NGF synthesis. The results showed that acute exposure of lipopolysaccharide-activated human monocyte/macrophage cultures to ethanol resulted in a sharp decrease in endogenously-produced NGF, which was associated with reduced expression of high-affinity NGF receptors on cell membranes and impaired production of TNF-α. These findings support the suggestion of a new mechanism by which ethanol can compromise the efficiency of the mononuclear phagocyte system in dealing with infection and host inflammatory response. NIAAA Glossary Terms:  immune response, ethanol, monocyte, macrophage, cytokines, nerve growth factors, receptors, inflammation, cytokines, tumor necrosis factor-alpha, lipopolysaccharide, cell culture study, phagocyte, infection, human study

Soon Ae Kim, Jong-Woo Kim, Ji-Young Song, Sunny Park, Hee Jae Lee, and Joo-Ho Chung.  Association of polymorphisms in nicotinic acetylcholine receptor α₄ subunit gene (CHRNA4), μ- µ-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.  Alcohol 34(2):115-120, October 2004.

Summary: Findings from several studies indicate that ethanol enhances the activity of α4β2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) modulates enhancement of nicotinic receptor function by ethanol. To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, the authors examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction–restriction fragment length polymorphism methods. They detected an association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype p = 0.023; allele frequency p = 0.047). The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes, such as alcohol metabolism-related genes [alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 3 (ADH3), and cytochrome P450 2E1 (CYP2E1)] and μ-opioid receptor gene (OPRM1), were studied. The polymorphisms of ADH2, ALDH2, and CYP2E1 were significantly different in alcoholic patients and control subjects without alcoholism, but ADH3 and OPRM1 did not differ between the two groups. NIAAA Glossary Terms:  ethanol, nicotinic receptor, cholinergic receptors, genetic polymorphism, genotype, allele, gene frequency, genetic trait, South Korea, AOD dependence, controlled study, polymerase chain reaction, alcohol dehydrogenases, aldehyde dehydrogenases, cytochrome P450 2E1, mu-opioid receptors, human study

Alexandr Parlesak, Michael Hans-Ulrich Billinger, Christian Schäfer, Heinz-Dieter Wehner, Christiane Bode, and Johann Christian Bode.  First-pass metabolism of ethanol in human beings: Effect of intravenous infusion of fructose.  Alcohol 34(2):121-125, October 2004.

Summary: Intravenous infusion of fructose has been shown to increase ethanol metabolism by enhancing the reoxidation of reduced nicotinamide adenine dinucleotide (NADH+). The present study investigated the effect of fructose infusion on first-pass ethanol metabolism in human volunteers. First-pass ethanol metabolism was significantly higher after fructose administration compared with findings for control experiments with an equimolar dose of glucose. Fructose is metabolized predominantly in the liver and presumably has virtually no effects in the stomach. Therefore the results of this study support the assumption that the stomach is the site of only a negligible part of first-pass ethanol metabolism. NIAAA Glossary Terms:  fructose, ethanol metabolism, oxidation-reduction, glucose, intravenous administration, controlled study, liver, stomach, human study

Vanessa Jimenez, Daniel P. Cardinali, Pilar Cano, María P. Alvarez, Carlos F. Reyes Toso, and Ana I. Esquifino.  Effect of ethanol on 24-hour hormonal changes in peripubertal male rats.  Alcohol 34(2):127-132, October 2004.

Summary: The effect of chronic (4 weeks) ethanol feeding on 24-hour variation of pituitary-testicular function was analyzed in peripubertal male Wistar rats by measuring circulating concentrations of prolactin (PL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (TS), and thyrotropin (TT). Animals were maintained under a 12-hour light,12-hour dark photoperiod and received a liquid diet for 4 weeks, starting on day 35 of life. The ethanol-fed group received a diet similar to that provided to control animals, except that maltose was replaced isocalorically with ethanol (36% of calories). Rats were killed at one of six times around the clock, beginning at zeitgeber time (ZT) 1 (ZT 0=lights on). In ethanol-fed rats PL secretion was augmented, whereas secretion of FSH, LH, TS, and TT was decreased. Significant changes in the 24-hour secretory pattern of circulating hormones occurred in ethanol-fed rats, including the appearance of two peaks (at ZT 1 and ZT 9), rather than one peak, of FSH during the inactive phase of the daily cycle, suppression of the maximum plasma LH concentration during the first part of the inactive phase, and appearance of a second peak of TS and PL d