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1
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Thomas LA, Hopkinson RJ. The biochemistry of the carcinogenic alcohol metabolite acetaldehyde. DNA Repair (Amst) 2024; 144:103782. [PMID: 39566398 DOI: 10.1016/j.dnarep.2024.103782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 10/14/2024] [Accepted: 10/30/2024] [Indexed: 11/22/2024]
Abstract
Acetaldehyde (AcH) is the first metabolite of ethanol and is proposed to be responsible for the genotoxic effects of alcohol consumption. As an electrophilic aldehyde, AcH can form multiple adducts with DNA and other biomolecules, leading to function-altering and potentially toxic and carcinogenic effects. In this review, we describe sources of AcH in humans, including AcH biosynthesis mechanisms, and outline the structures, properties and functions of AcH-derived adducts with biomolecules. We also describe human AcH detoxification mechanisms and discuss ongoing challenges in the field.
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Affiliation(s)
- Liam A Thomas
- Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, Leicester LE1 7RH, UK
| | - Richard J Hopkinson
- Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, Leicester LE1 7RH, UK.
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2
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Kong EQZ, Subramaniyan V, Lubau NSA. Uncovering the impact of alcohol on internal organs and reproductive health: Exploring TLR4/NF-kB and CYP2E1/ROS/Nrf2 pathways. Animal Model Exp Med 2024; 7:444-459. [PMID: 38853347 PMCID: PMC11369036 DOI: 10.1002/ame2.12436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 05/10/2024] [Indexed: 06/11/2024] Open
Abstract
This review delves into the detrimental impact of alcohol consumption on internal organs and reproductive health, elucidating the underlying mechanisms involving the Toll-like receptor 4 (TLR4)/Nuclear factor kappa light chain enhancer of activated B cells (NF-kB) pathway and the Cytochrome P450 2E1 (CYP2E1)/reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. The TLR4/NF-kB pathway, crucial for inflammatory and immune responses, triggers the production of pro-inflammatory agents and type-1 interferon, disrupting the balance between inflammatory and antioxidant responses when tissues are chronically exposed to alcohol. Alcohol-induced dysbiosis in gut microbes heightens gut wall permeability to pathogen-associated molecular patterns (PAMPs), leading to liver cell infection and subsequent inflammation. Concurrently, CYP2E1-mediated alcohol metabolism generates ROS, causing oxidative stress and damaging cells, lipids, proteins, and deoxyribonucleic acid (DNA). To counteract this inflammatory imbalance, Nrf2 regulates gene expression, inhibiting inflammatory progression and promoting antioxidant responses. Excessive alcohol intake results in elevated liver enzymes (ADH, CYP2E1, and catalase), ROS, NADH, acetaldehyde, and acetate, leading to damage in vital organs such as the heart, brain, and lungs. Moreover, alcohol negatively affects reproductive health by inhibiting the hypothalamic-pituitary-gonadal axis, causing infertility in both men and women. These findings underscore the profound health concerns associated with alcohol-induced damage, emphasizing the need for public awareness regarding the intricate interplay between immune responses and the multi-organ impacts of alcohol consumption.
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Affiliation(s)
- Eason Qi Zheng Kong
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSubang JayaSelangorMalaysia
| | - Vetriselvan Subramaniyan
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSubang JayaSelangorMalaysia
- Center for Global Health Research, Saveetha Medical CollegeSaveetha Institute of Medical and Technical SciencesChennaiTamil NaduIndia
| | - Natasha Sura Anak Lubau
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSubang JayaSelangorMalaysia
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3
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Burger K, Jung F, Staufer K, Ladurner R, Trauner M, Baumann A, Brandt A, Bergheim I. MASLD is related to impaired alcohol dehydrogenase (ADH) activity and elevated blood ethanol levels: Role of TNFα and JNK. Redox Biol 2024; 71:103121. [PMID: 38493749 PMCID: PMC10957403 DOI: 10.1016/j.redox.2024.103121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 03/19/2024] Open
Abstract
Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol consumption are discussed to contribute to disease development. To test the hypothesis that besides an enhanced gastrointestinal synthesis a diminished alcohol elimination through alcohol dehydrogenase (ADH) may also be critical herein, we determined fasting ethanol levels and ADH activity in livers and blood of MASLD patients and in wild-type ± anti-TNFα antibody (infliximab) treated and TNFα-/- mice fed a MASLD-inducing diet. Blood ethanol levels were significantly higher in patients and wild-type mice with MASLD while relative ADH activity in blood and liver tissue was significantly lower compared to controls. Both alterations were significantly attenuated in MASLD diet-fed TNFα-/- mice and wild-type mice treated with infliximab. Moreover, alcohol elimination was significantly impaired in mice with MASLD. In in vitro models, TNFα but not IL-1β or IL-6 significantly decreased ADH activity. Our data suggest that elevated ethanol levels in MASLD patients are related to TNFα-dependent impairments of ADH activity.
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Affiliation(s)
- Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Katharina Staufer
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria; Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Ruth Ladurner
- Department of General, Visceral and Transplant Surgery, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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Li Q, Wang O, Ji B, Zhao L, Zhao L. Alcohol, White Adipose Tissue, and Brown Adipose Tissue: Mechanistic Links to Lipogenesis and Lipolysis. Nutrients 2023; 15:2953. [PMID: 37447280 PMCID: PMC10346806 DOI: 10.3390/nu15132953] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
According to data from the World Health Organization, there were about 3 million deaths caused by alcohol consumption worldwide in 2016, of which about 50% were related to liver disease. Alcohol consumption interfering with the normal function of adipocytes has an important impact on the pathogenesis of alcoholic liver disease. There has been increasing recognition of the crucial role of adipose tissue in regulating systemic metabolism, far beyond that of an inert energy storage organ in recent years. The endocrine function of adipose tissue is widely recognized, and the significance of the proteins it produces and releases is still being investigated. Alcohol consumption may affect white adipose tissue (WAT) and brown adipose tissue (BAT), which interact with surrounding tissues such as the liver and intestines. This review briefly introduces the basic concept and classification of adipose tissue and summarizes the mechanism of alcohol affecting lipolysis and lipogenesis in WAT and BAT. The adipose tissue-liver axis is crucial in maintaining lipid homeostasis within the body. Therefore, this review also demonstrates the effects of alcohol consumption on the adipose tissue-liver axis to explore the role of alcohol consumption in the crosstalk between adipose tissue and the liver.
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Affiliation(s)
- Qing Li
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, China;
| | - Ou Wang
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China;
| | - Baoping Ji
- Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China;
| | - Liang Zhao
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, China;
| | - Lei Zhao
- School of Food and Health, Beijing Technology and Business University, Beijing 100048, China
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5
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Zhang L, Wang E, Peng G, Wang Y, Huang F. Comprehensive Proteome and Acetyl-Proteome Atlas Reveals Hepatic Lipid Metabolism in Layer Hens with Fatty Liver Hemorrhagic Syndrome. Int J Mol Sci 2023; 24:ijms24108491. [PMID: 37239836 DOI: 10.3390/ijms24108491] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
The feeding of high-energy and low-protein diets often induces fatty liver hemorrhagic syndrome (FLHS) in laying hens. However, the mechanism of hepatic fat accumulation in hens with FLHS remains uncertain. In this research, a comprehensive hepatic proteome and acetyl-proteome analysis was performed in both normal and FLHS-affected hens. The results indicated that the upregulated proteins were primarily associated with fat digestion and absorption, the biosynthesis of unsaturated fatty acids, and glycerophospholipid metabolism, while the downregulated proteins were mainly related to bile secretion and amino acid metabolism. Furthermore, the significant acetylated proteins were largely involved in ribosome and fatty acid degradation, and the PPAR signaling pathway, while the significant deacetylated proteins were related to valine, leucine, and isoleucine degradation in laying hens with FLHS. Overall, these results demonstrate that acetylation inhibits hepatic fatty acid oxidation and transport in hens with FLHS, and mainly exerts its effects by affecting protein activity rather than expression. This study provides new nutritional regulation options to alleviate FLHS in laying hens.
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Affiliation(s)
- Li Zhang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Enling Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Gang Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Yi Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Feiruo Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
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Yan C, Hu W, Tu J, Li J, Liang Q, Han S. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease. J Transl Med 2023; 21:300. [PMID: 37143126 PMCID: PMC10158301 DOI: 10.1186/s12967-023-04166-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/27/2023] [Indexed: 05/06/2023] Open
Abstract
Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. Many metabolic enzymes, including alcohol dehydrogenases such as ADH, CYP2E1, and CATacetaldehyde dehydrogenases ALDHsand nonoxidative metabolizing enzymes such as SULT, UGT, and FAEES, are involved in the metabolism of ethanol, the main component in alcoholic beverages. Ethanol consumption changes the functional or expression profiles of various regulatory factors, such as kinases, transcription factors, and microRNAs. Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. For example, ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. However, ALD therapies show low effectiveness. Therefore, this review summarizes ethanol metabolism pathways and highly influential pathogenic mechanisms and regulatory factors involved in ALD pathology with the aim of new therapeutic insights.
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Affiliation(s)
- Chuyun Yan
- Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Key Lab of Microanalytical Methods & Instrumentation, Department of Chemistry, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China
| | - Jinqi Tu
- The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College of Wuhu, Wannan Medical College, Wuhu, 241000, Anhui, China
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Key Lab of Microanalytical Methods & Instrumentation, Department of Chemistry, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China
| | - Shuxin Han
- Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830046, China.
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George TE, Okhiai PO, Osonuga IO, Oyesola OA. Protective Effect of Commercial Grade Vitamin C against Alcohol-induced Testicular Damage in Male Wistar Rats. J Hum Reprod Sci 2023; 16:99-105. [PMID: 37547092 PMCID: PMC10404017 DOI: 10.4103/jhrs.jhrs_39_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/28/2023] [Accepted: 05/30/2023] [Indexed: 08/08/2023] Open
Abstract
Background Alcohol consumption has a negative effect on male fertility, but Vitamin C may be able to alleviate this effect. Aims In this study, the protective effect of Vitamin C against alcohol-induced testicular damage in adult male Wistar rats was evaluated. Settings and Design This study was conducted in a University setting. Following a 14-day acclimatisation period, forty adult male Wistar rats were randomly divided into eight groups of five rats. The control group received only food and water, test group B received alcohol only, test group C to E received different doses of Vitamin C, test group F to G received different doses of Vitamin C and alcohol. Materials and Methods After a 21-day treatment period, the testis were harvested and analysed for sperm parameters, antioxidant enzyme activity, level of lipid peroxidation and histopathological changes. Statistical Analysis Used All analyses was performed using SPSS (version 16) and Microsoft Excel (2019) using Student's t-test. Results The results showed that in groups administered with alcohol only, there was a decrease in sperm count. Sperm motility, morphology, viability and antioxidant enzyme activity, but increase in the level of lipid peroxidation. In groups treated with Vitamin C and alcohol, there was improvement in the sperm parameters, antioxidant enzymes activity and a decrease and decrease in lipid peroxidation. Furthermore, in the histology of the testis, regenerative changes were seen. Conclusion The chronic consumption of alcohol can have a deleterious effect on the testis, but commercial-grade Vitamin C can reverse these effects.
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Affiliation(s)
- Taiwo Emmanuel George
- Department of Physiology, Faculty of Basic Medical Sciences, Olabisi Onabanjo University, Ikeji-Arakiji, Osun State, Nigeria
| | - Peter Okhemukhokho Okhiai
- Department of Nursing Sciences, College of Health Sciences, Joseph Ayo Babalola University, Ikeji-Arakiji, Osun State, Nigeria
| | - Ifabunmi Oduyemi Osonuga
- Department of Physiology, Faculty of Basic Medical Sciences, Olabisi Onabanjo University, Ikeji-Arakiji, Osun State, Nigeria
| | - Olusoji Adebusoye Oyesola
- Department of Physiology, Faculty of Basic Medical Sciences, Olabisi Onabanjo University, Ikeji-Arakiji, Osun State, Nigeria
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8
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miR-29c-3p promotes alcohol dehydrogenase gene cluster expression by activating an ADH6 enhancer. Biochem Pharmacol 2022; 203:115182. [PMID: 35868429 DOI: 10.1016/j.bcp.2022.115182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 12/18/2022]
Abstract
Alcohol dehydrogenases (ADHs) play vital roles in alcohol metabolism and alcohol toxicity, yet little is known about microRNA-mediated regulation of the ADH gene cluster. Here, we showed that miR-29c activated ADH gene cluster transcription by targeting an enhancer element within the ADH6 gene. miR-29c is differentially expressed in alcoholic liver disease. Following biochemical and molecular evidence demonstrated that miR-29c increased ADH6 mRNA and protein levels without affecting the stability of the ADH6 transcript. Further evidence showed that exogenous miR-29c translocated into the nucleus and then unconventionally bound an enhancer element within the ADH6 gene. Luciferase reporter assay and chromatin immunoprecipitation data indicated that miR-29c activated the enhancer and increased the enrichment of RNA polymerase II at the promoter regions of ADH1A, ADH1B, ADH1C, ADH4, and ADH6. Finally, exogenous miR-29c transfection promoted the expression of ADH1A, ADH1B, ADH1C, and ADH4 pre-mRNA and mRNA transcripts from the ADH gene cluster. In conclusion, our data suggest that miR-29c might be a novel epigenetic regulator involved in ADH gene cluster activation.
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9
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Ethanol Metabolism in the Liver, the Induction of Oxidant Stress, and the Antioxidant Defense System. Antioxidants (Basel) 2022; 11:antiox11071258. [PMID: 35883749 PMCID: PMC9312216 DOI: 10.3390/antiox11071258] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
The liver metabolizes ethanol through three enzymatic pathways: alcohol dehydrogenase (ADH), cytochrome p450 (also called MEOS), and catalase. Alcohol dehydrogenase class I (ADH1) is considered the most important enzyme for the metabolism of ethanol, MEOS and catalase (CAT) are considered minor alternative pathways. However, contradicting experiments suggest that the non-ADH1 pathway may have a greater relevance for the metabolism of ethanol than previously thought. In some conditions, ethanol is predominately metabolized to acetaldehyde via cytochrome P450 family 2 (CYP2E1), which is involved in the generation of reactive oxygen species (ROS), mainly through electron leakage to oxygen to form the superoxide (O2•−) radical or in catalyzed lipid peroxidation. The CAT activity can also participate in the ethanol metabolism that produces ROS via ethanol directly reacting with the CAT-H2O2 complex, producing acetaldehyde and water and depending on the H2O2 availability, which is the rate-limiting component in ethanol peroxidation. We have shown that CAT actively participates in lactate-stimulated liver ethanol oxidation, where the addition of lactate generates H2O2, which is used by CAT to oxidize ethanol to acetaldehyde. Therefore, besides its known role as a catalytic antioxidant component, the primary role of CAT could be to function in the metabolism of xenobiotics in the liver.
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10
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Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H. Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes. Xenobiotica 2021; 51:582-589. [PMID: 33455497 DOI: 10.1080/00498254.2021.1875515] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tolbutamide is an oral anti-hyperglycaemic agent used to treat non-insulin-dependent diabetes mellitus with species-dependent metabolic profiles. In this study, we investigated tolbutamide metabolism in chimeric TK-NOG mice transplanted with human hepatocytes (humanised-liver mice).Substantial 4-hydroxytolbutamide and 4-carboxytolbutamide production was observed in hepatocytes from humanised-liver mice (Hu-Liver cells) and humans, whereas 4-carboxytolbutamide production was not detected in mouse hepatocytes. In Hu-Liver cells, 4-hydroxytolbutamide formation was inhibited by sulfaphenazole (CYP2C9 inhibitor), whereas 4-carboxytolbutamide formation was inhibited by raloxifene/ethinyloestradiol (aldehyde oxidase inhibitor) and disulfiram (aldehyde dehydrogenase inhibitor).After a single oral dose of tolbutamide (10 mg/kg), the plasma levels of 4-carboxytolbutamide and p-tolylsulfonylurea were higher in humanised-liver mice than in TK-NOG mice. Urinary excretion was the predominant route (>99% of unchanged drug and metabolites detected in excreta) of elimination in both groups. 4-Carboxytolbutamide was the most abundant metabolite in humanised-liver mouse urine, as similarly reported for humans, whereas 4-hydroxytolbutamide was predominantly excreted in TK-NOG mouse urine.These results suggest that humanised-liver mice might represent a suitable animal model for studying the successive oxidative metabolism of tolbutamide by multiple drug-metabolising enzymes. Future work is warranted to study the general nature of primary alcohol metabolism using humanised-liver mice.
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Affiliation(s)
- Shotaro Uehara
- Central Institute for Experimental Animals, Kawasaki, Japan
| | - Nao Yoneda
- Central Institute for Experimental Animals, Kawasaki, Japan
| | | | - Hiroshi Yamazaki
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan
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Penaloza CG, Cruz M, Germain G, Jabeen S, Javdan M, Lockshin RA, Zakeri Z. Higher sensitivity of female cells to ethanol: methylation of DNA lowers Cyp2e1, generating more ROS. Cell Commun Signal 2020; 18:111. [PMID: 32653010 PMCID: PMC7353761 DOI: 10.1186/s12964-020-00616-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/27/2020] [Indexed: 01/21/2023] Open
Abstract
Background Cells taken from mouse embryos before sex differentiation respond to insults according to their chromosomal sex, a difference traceable to differential methylation. We evaluated the mechanism for this difference in the controlled situation of their response to ethanol. Methods We evaluated the expression of mRNA for alcohol dehydrogenase (ADH), aldehyde dehyrogenases (ALDH), and a cytochrome P450 isoenzyme (Cyp2e1) in male and female mice, comparing the expressions to toxicity under several experimental conditions evaluating redox and other states. Results Females are more sensitive to ethanol. Disulfiram, which inhibits alcohol dehydrogenase (ADH), increases cell death in males, eliminating the sex dimorphism. The expressions ADH Class 1 to 4 and ALDH Class 1 and 2 do not differ by sex. However, females express approximately 8X more message for Cyp2e1, an enzyme in the non-canonical pathway. Female cells produce approximately 15% more ROS (reactive oxygen species) than male cells, but male cells contain approximately double the concentration of GSH, a ROS scavenger. Scavenging ROS with N-acetyl cysteine reduces cell death and eliminates sex dimorphism. Finally, since many of the differences in gene expression derive from methylation of DNA, we exposed cells to the methyltransferase inhibitor 5-aza- 2-deoxycytidine; blocking methylation eliminates both the difference in expression of Cyp2e1 and cell death. Conclusion We conclude that the sex-differential cell death caused by ethanol derives from sex dimorphic methylation of Cyp2e1 gene, resulting in generation of more ROS.
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Affiliation(s)
- Carlos G Penaloza
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA.,Present Address: Chancellor's Office, Leeward Community College, Pearl City, HI, USA
| | - Mayra Cruz
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA
| | - Gabrielle Germain
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA
| | - Sidra Jabeen
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA
| | - Mohammad Javdan
- Queensborough Community College, City College of New York, Bayside, NY, USA
| | - Richard A Lockshin
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA.
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12
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Haseba T, Okuda T, Maruyama M, Akimoto T, Duester G, Ohno Y. Roles of Two Major Alcohol Dehydrogenases, ADH1 (Class I) and ADH3 (Class III), in the Adaptive Enhancement of Alcohol Metabolism Induced by Chronic Alcohol Consumption in Mice. Alcohol Alcohol 2020; 55:11-19. [PMID: 31825074 DOI: 10.1093/alcalc/agz091] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2019] [Indexed: 12/18/2022] Open
Abstract
AIMS It is still unclear which enzymes contribute to the adaptive enhancement of alcohol metabolism by chronic alcohol consumption (CAC). ADH1 (Class I) has the lowest Km for ethanol and the highest sensitivity for 4-methylpyrazole (4MP) among ADH isozymes, while ADH3 (Class III) has the highest Km and the lowest sensitivity. We investigated how these two major ADHs relate to the adaptive enhancement of alcohol metabolism. METHODS Male mice with different ADH genotypes (WT, Adh1-/- and Adh3-/-) were subjected to CAC experiment using a 10% ethanol solution for 1 month. Alcohol elimination rate (AER) was measured after ethanol injection at a 4.0 g/kg dose. 4MP-sensitive and -insensitive AERs were measured by the simultaneous administration of 4MP at a dose of 0.5 mmol/kg in order to estimate ADH1 and non-ADH1 pathways. RESULTS AER was enhanced by CAC in all ADH genotypes, especially more than twofold in Adh1-/- mice, with increasing ADH1 and/or ADH3 liver contents, but not CYP2E1 content. 4MP-sensitive AER was also increased by CAC in WT and Adh3-/- strains, which was greater in Adh3-/- than in WT mice. The sensitive AER was increased even in Adh1-/- mice probably due to the increase in ADH3, which is semi-sensitive for 4MP. 4MP-insensitive AER was also increased in WT and Adh1-/- by CAC, but not in Adh3-/- mice. CONCLUSION ADH1 contributes to the enhancement of alcohol metabolism by CAC, particularly in the absence of ADH3. ADH3 also contributes to the enhancement as a non-ADH1 pathway, especially in the absence of ADH1.
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Affiliation(s)
- Takeshi Haseba
- Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.,Department of Forensic Medicine, Kanagawa Dental University, 8 Inaokacho, Yokosuka 238-8580, Japan
| | - Takahisa Okuda
- Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Motoyo Maruyama
- Division of Laboratory Animal Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.,Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Toshio Akimoto
- Division of Laboratory Animal Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Gregg Duester
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901N Torrey Pines Road, La Jolla, CA 92037, USA
| | - Youkichi Ohno
- Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
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Okuda T, Naruo M, Iijima O, Igarashi T, Katsuyama M, Maruyama M, Akimoto T, Ohno Y, Haseba T. The Contribution of Alcohol Dehydrogenase 3 to the Development of Alcoholic Osteoporosis in Mice. J NIPPON MED SCH 2018; 85:322-329. [DOI: 10.1272/jnms.jnms.2018_85-52] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
| | | | - Osamu Iijima
- Office for Research Administrative Support, Center for Strategic Research Initiative, Nippon Medical School
| | | | | | - Motoyo Maruyama
- Division of Laboratory Animal Science, Nippon Medical School
| | - Toshio Akimoto
- Division of Laboratory Animal Science, Nippon Medical School
| | | | - Takeshi Haseba
- Department of Legal Medicine, Nippon Medical School
- Department of Legal Medicine, Kanagawa Dental University
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14
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Edenberg HJ, McClintick JN. Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review. Alcohol Clin Exp Res 2018; 42:2281-2297. [PMID: 30320893 PMCID: PMC6286250 DOI: 10.1111/acer.13904] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/07/2018] [Indexed: 12/20/2022]
Abstract
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
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Affiliation(s)
- Howard J. Edenberg
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Jeanette N. McClintick
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
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15
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Zhu B, He H, Hou T. A Comprehensive Review of Corn Protein-derived Bioactive Peptides: Production, Characterization, Bioactivities, and Transport Pathways. Compr Rev Food Sci Food Saf 2018; 18:329-345. [DOI: 10.1111/1541-4337.12411] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/29/2018] [Accepted: 10/29/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Biyang Zhu
- College of Food Science and Technology; Huazhong Agricultural Univ.; Wuhan 430070 China
- Key Lab of Environment Correlative Dietology (Huazhong Agricultural Univ.); Ministry of Education; Wuhan 43000 China
| | - Hui He
- College of Food Science and Technology; Huazhong Agricultural Univ.; Wuhan 430070 China
- Key Lab of Environment Correlative Dietology (Huazhong Agricultural Univ.); Ministry of Education; Wuhan 43000 China
| | - Tao Hou
- College of Food Science and Technology; Huazhong Agricultural Univ.; Wuhan 430070 China
- Key Lab of Environment Correlative Dietology (Huazhong Agricultural Univ.); Ministry of Education; Wuhan 43000 China
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16
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Zhang Y, Wang C, Yu B, Jiang JD, Kong WJ. Gastrodin Protects against Ethanol-Induced Liver Injury and Apoptosis in HepG2 Cells and Animal Models of Alcoholic Liver Disease. Biol Pharm Bull 2018; 41:670-679. [DOI: 10.1248/bpb.b17-00825] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yong Zhang
- Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Can Wang
- State Key Laboratory of Bioactive Natural Products and Function, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Bin Yu
- Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Jian-Dong Jiang
- State Key Laboratory of Bioactive Natural Products and Function, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Wei-Jia Kong
- Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College
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17
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Peana AT, Sánchez-Catalán MJ, Hipólito L, Rosas M, Porru S, Bennardini F, Romualdi P, Caputi FF, Candeletti S, Polache A, Granero L, Acquas E. Mystic Acetaldehyde: The Never-Ending Story on Alcoholism. Front Behav Neurosci 2017; 11:81. [PMID: 28553209 PMCID: PMC5425597 DOI: 10.3389/fnbeh.2017.00081] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 04/18/2017] [Indexed: 12/12/2022] Open
Abstract
After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic.
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Affiliation(s)
| | - María J. Sánchez-Catalán
- Department of Pharmacy, Pharmaceutical Technology and Parasitology, University of ValenciaValència, Spain
| | - Lucia Hipólito
- Department of Pharmacy, Pharmaceutical Technology and Parasitology, University of ValenciaValència, Spain
| | - Michela Rosas
- Department of Life and Environmental Sciences, University of CagliariCagliari, Italy
| | - Simona Porru
- Department of Life and Environmental Sciences, University of CagliariCagliari, Italy
| | | | - Patrizia Romualdi
- Department of Pharmacy and Biotechnology, University of BolognaBologna, Italy
| | - Francesca F. Caputi
- Department of Pharmacy and Biotechnology, University of BolognaBologna, Italy
| | - Sanzio Candeletti
- Department of Pharmacy and Biotechnology, University of BolognaBologna, Italy
| | - Ana Polache
- Department of Pharmacy, Pharmaceutical Technology and Parasitology, University of ValenciaValència, Spain
| | - Luis Granero
- Department of Pharmacy, Pharmaceutical Technology and Parasitology, University of ValenciaValència, Spain
| | - Elio Acquas
- Department of Life and Environmental Sciences, University of CagliariCagliari, Italy
- Centre of Excellence on Neurobiology of Addiction, University of CagliariCagliari, Italy
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18
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Peana AT, Rosas M, Porru S, Acquas E. From Ethanol to Salsolinol: Role of Ethanol Metabolites in the Effects of Ethanol. J Exp Neurosci 2016; 10:137-146. [PMID: 27891052 PMCID: PMC5117487 DOI: 10.4137/jen.s25099] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/13/2016] [Accepted: 11/03/2016] [Indexed: 12/29/2022] Open
Abstract
In spite of the global reputation of ethanol as the psychopharmacologically active ingredient of alcoholic drinks, the neurobiological basis of the central effects of ethanol still presents some dark sides due to a number of unanswered questions related to both its precise mechanism of action and its metabolism. Accordingly, ethanol represents the interesting example of a compound whose actions cannot be explained as simply due to the involvement of a single receptor/neurotransmitter, a scenario further complicated by the robust evidence that two main metabolites, acetaldehyde and salsolinol, exert many effects similar to those of their parent compound. The present review recapitulates, in a perspective manner, the major and most recent advances that in the last decades boosted a significant growth in the understanding on the role of ethanol metabolism, in particular, in the neurobiological basis of its central effects.
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Affiliation(s)
- Alessandra T Peana
- Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
| | - Michela Rosas
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Simona Porru
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Elio Acquas
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.; Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Cagliari, Italy
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19
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Seo W, Jeong WI. Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease? World J Gastroenterol 2016; 22:1348-1356. [PMID: 26819504 PMCID: PMC4721970 DOI: 10.3748/wjg.v22.i4.1348] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 09/28/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease (ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, microRNA, and lipid-originated metabolites (retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells (hepatocytes). Therefore, understanding the comprehensive roles of hepatic non-parenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of non-parenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD.
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20
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Tran S, Nowicki M, Facciol A, Chatterjee D, Gerlai R. Ethanol-Induced ADH Activity in Zebrafish: Differential Concentration-Dependent Effects on High- Versus Low-Affinity ADH Enzymes. Zebrafish 2016; 13:75-8. [PMID: 26741829 DOI: 10.1089/zeb.2015.1173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Zebrafish express enzymes that metabolize ethanol in a manner comparable to that of mammals, including humans. We previously demonstrated that acute ethanol exposure increases alcohol dehydrogenase (ADH) activity in an inverted U-shaped dose-dependent manner. It was hypothesized that the biphasic dose-response was due to the increased activity of a high-affinity ADH isoform following exposure to low concentrations of ethanol and increased activity of a low-affinity ADH isoform following exposure to higher concentrations of ethanol. To test this hypothesis, we exposed zebrafish to different concentrations of ethanol (0%, 0.25%, 0.5%, and 1.0% v/v) for 30 min and measured the total ADH activity in the zebrafish liver. However, we also repeated this enzyme activity assay using a low concentration of the substrate (ethanol) to determine the activity of high-affinity ADH isoforms. We found that total ADH activity in response to ethanol induces an inverted U-shaped dose-response similar to our previous study. Using a lower substrate level in our enzyme assay targeting high-affinity isozymes, we found a similar dose-response. However, the difference in activity between the high and low substrate assays (high substrate activity - low substrate activity), which provide an index of activity for low-affinity ADH isoforms, revealed no significant effect of ethanol exposure. Our results suggest that the inverted U-shaped dose-response for total ADH activity in response to ethanol is driven primarily by high-affinity isoforms of ADH.
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Affiliation(s)
- Steven Tran
- 1 Department of Cell and Systems Biology, University of Toronto , Toronto, Ontario, Canada
| | - Magda Nowicki
- 2 Department of Psychology, University of Toronto Mississauga , Mississauga, Ontario, Canada
| | - Amanda Facciol
- 2 Department of Psychology, University of Toronto Mississauga , Mississauga, Ontario, Canada
| | - Diptendu Chatterjee
- 2 Department of Psychology, University of Toronto Mississauga , Mississauga, Ontario, Canada
| | - Robert Gerlai
- 1 Department of Cell and Systems Biology, University of Toronto , Toronto, Ontario, Canada .,2 Department of Psychology, University of Toronto Mississauga , Mississauga, Ontario, Canada
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21
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She X, Wang F, Ma J, Chen X, Ren D, Lu J. In vitroantioxidant and protective effects of corn peptides on ethanol-induced damage in HepG2 cells. FOOD AGR IMMUNOL 2015. [DOI: 10.1080/09540105.2015.1079597] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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22
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Lyon KF, Strong CL, Schooler SG, Young RJ, Roy N, Ozar B, Bachmeier M, Rajasekaran S, Schiller MR. Natural variability of minimotifs in 1092 people indicates that minimotifs are targets of evolution. Nucleic Acids Res 2015; 43:6399-412. [PMID: 26068475 PMCID: PMC4513861 DOI: 10.1093/nar/gkv580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 04/17/2015] [Accepted: 05/21/2015] [Indexed: 01/05/2023] Open
Abstract
Since the function of a short contiguous peptide minimotif can be introduced or eliminated by a single point mutation, these functional elements may be a source of human variation and a target of selection. We analyzed the variability of ∼300 000 minimotifs in 1092 human genomes from the 1000 Genomes Project. Most minimotifs have been purified by selection, with a 94% invariance, which supports important functional roles for minimotifs. Minimotifs are generally under negative selection, possessing high genomic evolutionary rate profiling (GERP) and sitewise likelihood-ratio (SLR) scores. Some are subject to neutral drift or positive selection, similar to coding regions. Most SNPs in minimotif were common variants, but with minor allele frequencies generally <10%. This was supported by low substation rates and few newly derived minimotifs. Several minimotif alleles showed different intercontinental and regional geographic distributions, strongly suggesting a role for minimotifs in adaptive evolution. We also note that 4% of PTM minimotif sites in histone tails were common variants, which has the potential to differentially affect DNA packaging among individuals. In conclusion, minimotifs are a source of functional genetic variation in the human population; thus, they are likely to be an important target of selection and evolution.
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Affiliation(s)
- Kenneth F Lyon
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Christy L Strong
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Steve G Schooler
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Richard J Young
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269-2155, USA
| | - Nervik Roy
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Brittany Ozar
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Mark Bachmeier
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
| | - Sanguthevar Rajasekaran
- Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269-2155, USA
| | - Martin R Schiller
- Nevada Institute of Personalized Medicine and School of Life Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4004, USA
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23
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Dorokhov YL, Shindyapina AV, Sheshukova EV, Komarova TV. Metabolic methanol: molecular pathways and physiological roles. Physiol Rev 2015; 95:603-44. [PMID: 25834233 DOI: 10.1152/physrev.00034.2014] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde.
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Affiliation(s)
- Yuri L Dorokhov
- A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia; and N. I. Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia
| | - Anastasia V Shindyapina
- A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia; and N. I. Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia
| | - Ekaterina V Sheshukova
- A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia; and N. I. Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia
| | - Tatiana V Komarova
- A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia; and N. I. Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russia
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24
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Zhang W, Zhong W, Sun X, Sun Q, Tan X, Li Q, Sun X, Zhou Z. Visceral white adipose tissue is susceptible to alcohol-induced lipodystrophy in rats: role of acetaldehyde. Alcohol Clin Exp Res 2015; 39:416-23. [PMID: 25703837 DOI: 10.1111/acer.12646] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/18/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic alcohol exposure causes lipid dyshomeostasis at the adipose-liver axis, reducing lipid storage in white fat and increasing lipid deposit in the liver. Previous studies have shown that visceral fat, rather than subcutaneous fat, is a risk factor for metabolic diseases. This study was conducted to determine whether chronic alcohol exposure differentially affects lipid metabolism in visceral (epididymal) and subcutaneous fat, and the mechanisms underlying the alcohol effects. METHODS Male Wistar rats were pair-fed the Lieber-DeCarli control or alcohol liquid diet for 12 weeks to determine the effects of alcohol on the white fat. Tissue explants culture and 3T3-L1 culture were conducted to define the role of acetaldehyde in alcohol-induced adipose tissue dysfunction. RESULTS Chronic alcohol feeding significantly reduced visceral fat mass and down-regulated peroxisome proliferator activator receptor-γ and CCAAT/enhancer binding protein-α, 2 important transcription factors in regulation of lipogenesis. The protein levels of lipogenic enzymes including phospho-ATP-citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, lipin1, and diacylglycerol acyltransferase 2 in the visceral fat were reduced. In contrast, chronic alcohol exposure did not affect subcutaneous fat mass and had less effect on the protein levels of lipogenic enzymes and regulators. Accordingly, the visceral fat showed a lower protein level of aldehyde detoxification enzymes compared to the subcutaneous fat. Acetaldehyde treatment to either visceral fat explants or 3T3-L1 adipocytes produced similar effects on lipogenic enzymes and regulators as observed in animal model. CONCLUSIONS These results demonstrated that visceral fat is more susceptible to alcohol toxicity compared to subcutaneous fat, and disruption of adipose lipogenesis contributes to the pathogenesis of alcoholic lipodystrophy.
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Affiliation(s)
- Wenliang Zhang
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, North Carolina
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25
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Tran S, Nowicki M, Chatterjee D, Gerlai R. Acute and chronic ethanol exposure differentially alters alcohol dehydrogenase and aldehyde dehydrogenase activity in the zebrafish liver. Prog Neuropsychopharmacol Biol Psychiatry 2015; 56:221-6. [PMID: 25290637 DOI: 10.1016/j.pnpbp.2014.09.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/16/2014] [Accepted: 09/29/2014] [Indexed: 01/02/2023]
Abstract
Chronic ethanol exposure paradigms have been successfully used in the past to induce behavioral and central nervous system related changes in zebrafish. However, it is currently unknown whether chronic ethanol exposure alters ethanol metabolism in adult zebrafish. In the current study we examine the effect of acute ethanol exposure on adult zebrafish behavioral responses, as well as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity in the liver. We then examine how two different chronic ethanol exposure paradigms (continuous and repeated ethanol exposure) alter behavioral responses and liver enzyme activity during a subsequent acute ethanol challenge. Acute ethanol exposure increased locomotor activity in a dose-dependent manner. ADH activity was shown to exhibit an inverted U-shaped curve and ALDH activity was decreased by ethanol exposure at all doses. During the acute ethanol challenge, animals that were continuously housed in ethanol exhibited a significantly reduced locomotor response and increased ADH activity, however, ALDH activity did not change. Zebrafish that were repeatedly exposed to ethanol demonstrated a small but significant attenuation of the locomotor response during the acute ethanol challenge but ADH and ALDH activity was similar to controls. Overall, we identified two different chronic ethanol exposure paradigms that differentially alter behavioral and physiological responses in zebrafish. We speculate that these two paradigms may allow dissociation of central nervous system-related and liver enzyme-dependent ethanol induced changes in zebrafish.
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Affiliation(s)
- Steven Tran
- Department of Cell and Systems Biology, University of Toronto Mississauga, Canada.
| | - Magda Nowicki
- Department of Psychology, University of Toronto Mississauga, Canada
| | | | - Robert Gerlai
- Department of Cell and Systems Biology, University of Toronto Mississauga, Canada; Department of Psychology, University of Toronto Mississauga, Canada
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26
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Heit C, Dong H, Chen Y, Shah YM, Thompson DC, Vasiliou V. Transgenic mouse models for alcohol metabolism, toxicity, and cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:375-87. [PMID: 25427919 PMCID: PMC4323349 DOI: 10.1007/978-3-319-09614-8_22] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remain to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol-metabolizing enzymes and GSH-synthesizing enzymes and their relevance to alcohol research.
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Affiliation(s)
- Claire Heit
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA
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Zuo L, Lu L, Tan Y, Pan X, Cai Y, Wang X, Hong J, Zhong C, Wang F, Zhang XY, Vanderlinden LA, Tabakoff B, Luo X. Genome-wide association discoveries of alcohol dependence. Am J Addict 2014; 23:526-39. [PMID: 25278008 PMCID: PMC4187224 DOI: 10.1111/j.1521-0391.2014.12147.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 04/17/2014] [Accepted: 05/12/2014] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. METHODS We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p < 5 × 10(-8) ); top-ranked associations in an individual sample (p < 10(-5) ) that were nominally replicated in other samples (p < .05); and nominally replicable associations across at least three independent GWAS samples (p < .05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed. RESULTS The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10(-8) ) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG-PECR or PKNOX2 were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10(-8) ) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L-CMTM8 or MAP3K9-PCNX were suggestive (5 × 10(-8) < p < 10(-5) ) in some samples, and nominally replicable in other samples. The associations with the variants at HTR7 and OPA3 were nominally replicable across at least three independent GWAS samples (10(-5) < p < .05). Some risk variants at the ADH cluster, SERINC2, KIAA0040, NRD1, and HTR7 had potential biological functions. CONCLUSION The most robust risk locus was the ADH cluster. SERINC2, KIAA0040, NRD1, and HTR7 were also likely to play important roles in alcohol dependence. PKNOX2, MREG, PECR, GPD1L, CMTM8, MAP3K9, PCNX, and OPA3 might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post-GWAS follow-up studies on alcohol dependence.
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Affiliation(s)
- Lingjun Zuo
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Yunlong Tan
- Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China
| | - Xinghua Pan
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - Yiqiang Cai
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Xiaoping Wang
- Department of Neurology, First People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jiang Hong
- Department of Internal Medicine, First People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Chunlong Zhong
- Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Fei Wang
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Xiang-yang Zhang
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA
| | | | - Boris Tabakoff
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Xingguang Luo
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
- Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China
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Nan YM, Wang RQ, Fu N. Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease. World J Gastroenterol 2014; 20:8055-8060. [PMID: 25009377 PMCID: PMC4081676 DOI: 10.3748/wjg.v20.i25.8055] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/02/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.
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Silva RDC, Carmo LST, Luis ZG, Silva LP, Scherwinski-Pereira JE, Mehta A. Proteomic identification of differentially expressed proteins during the acquisition of somatic embryogenesis in oil palm (Elaeis guineensis Jacq.). J Proteomics 2014; 104:112-27. [PMID: 24675181 DOI: 10.1016/j.jprot.2014.03.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 02/24/2014] [Accepted: 03/12/2014] [Indexed: 01/03/2023]
Abstract
UNLABELLED In the present study we have identified and characterized the proteins expressed during different developmental stages of Elaeis guineensis calli obtained from zygotic embryos. We were interested in the possible proteomic changes that would occur during the acquisition of somatic embryogenesis and therefore samples were collected from zygotic embryos (E1), swollen explants 14days (E2) in induction medium, primary callus (E3), and pro-embryogenic callus (E4). The samples were grinded in liquid nitrogen, followed by total protein extraction using phenol and extraction buffer. Proteins were analyzed by two-dimensional electrophoresis (2-DE) and the differentially expressed protein spots were analyzed by MALDI-TOF mass spectrometry (MS and MS/MS). Interestingly, we have identified proteins, which can be used as potential candidates for future studies aiming at the development of biomarkers for embryogenesis acquisition and for the different stages leading to pro-embryogenic callus formation such as type IIIa membrane protein cp-wap13, fructokinase and PR proteins. The results obtained shed some light on the biochemical events involved in the process of somatic embryogenesis of E. guineensis obtained from zygotic embryos. The use of stage-specific protein markers can help monitor cell differentiation and contribute to improve the protocols for successfully cloning the species. BIOLOGICAL SIGNIFICANCE Understanding the fate and dynamics of cells and tissues during callus formation is essential to understand totipotency and the mechanisms involved during acquisition of somatic embryogenesis (SE). In this study we have investigated the early stages of somatic embryogenesis induction in oil palm and have identified potential markers as well as proteins potentially involved in embryogenic competence acquisition. The use of these proteins can help improve tissue culture protocols in order to increase regeneration rates. This article is part of a Special Issue entitled: Environmental and structural proteomics.
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Affiliation(s)
- Rafael de Carvalho Silva
- PPGBIOTEC, Departamento de Biologia, Universidade Federal do Amazonas, CEP 69077-000, Manaus, AM, Brazil
| | | | - Zanderluce Gomes Luis
- PPGBOT, Departamento de Botanica, Instituto de Biologia, Universidade de Brasilia, CEP 70910-900, Brasília, DF, Brazil
| | - Luciano Paulino Silva
- Embrapa Recursos Genéticos e Biotecnologia, Av. W5 Norte Final, CEP 70770-917, Brasília, DF, Brazil
| | - Jonny Everson Scherwinski-Pereira
- Embrapa Recursos Genéticos e Biotecnologia, Av. W5 Norte Final, CEP 70770-917, Brasília, DF, Brazil; PPGBOT, Departamento de Botanica, Instituto de Biologia, Universidade de Brasilia, CEP 70910-900, Brasília, DF, Brazil.
| | - Angela Mehta
- Embrapa Recursos Genéticos e Biotecnologia, Av. W5 Norte Final, CEP 70770-917, Brasília, DF, Brazil.
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Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol 2014; 48:1-17. [PMID: 24447472 DOI: 10.1016/j.alcohol.2013.09.045] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 09/16/2013] [Accepted: 09/18/2013] [Indexed: 11/23/2022]
Abstract
Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol's acute and long-term pharmacological consequences.
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Rendón-Ramírez A, Cortés-Couto M, Martínez-Rizo AB, Muñiz-Hernández S, Velázquez-Fernández JB. Oxidative damage in young alcohol drinkers: A preliminary study. Alcohol 2013; 47:501-4. [PMID: 24080163 DOI: 10.1016/j.alcohol.2013.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 08/08/2013] [Accepted: 08/12/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND Oxidative damage (OD) biomarkers have been used to evaluate metabolic stress undergone by alcoholic individuals. In alcoholic patients, these biomarkers are usually measured at late stages, i.e., when the alcoholic patients are showing clear signs of impaired hepatic function. OD biomarkers are sensitive indicators of impaired metabolic function, and might be useful in early stages of alcohol consumption to identify individuals who are at greater risk of damage in later stages of alcohol consumption. The aim of the present work was to evaluate some OD biomarkers in young people at early stages of alcohol consumption. METHODS The study was carried out in a group of young people (18-23 years old) who drank alcohol, Youngsters Exposed to Alcohol (YEA) with an average intake of 118 g of ethanol/week, and a control group (CG) of non-drinkers. Blood counts, alcohol dehydrogenase (ADH) activity, glutathione peroxidase (GSH-Px) activity, oxidative damage to DNA, and lipid peroxidation were determined in both groups. RESULTS The anthropometric and blood parameters of both groups were similar and no clinical symptoms of hepatic damage were observed. Nevertheless, ADH activity, lipid peroxidation, and percentage of damaged DNA cells were higher in the YEA group than in the control group. In contrast, GSH-Px activity was lower in the YEA group than in the control group. CONCLUSION Alteration in OD biomarkers can be found in individuals with 4-5 years of alcohol drinking history. To our knowledge, this is the first study giving evidence of OD in individuals at early stages of alcohol abuse.
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Affiliation(s)
- Adela Rendón-Ramírez
- Unidad de Biofísica (Centro Mixto CSIC-UPV, EHU), Universidad del País Vasco, Aptdo. 644, 48080 Leioa, Spain.
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Tokuda K, Izumi Y, Zorumski CF. Locally-generated Acetaldehyde Contributes to the Effects of Ethanol on Neurosteroids and LTP in the Hippocampus. ACTA ACUST UNITED AC 2013; 1:138-147. [PMID: 24455167 DOI: 10.1111/ncn3.39] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND As severe alcohol intoxication impairs memory function, a high concentration of ethanol (60 mM) acutely inhibits long-term potentiation (LTP), a cellular model of learning and memory, in rat hippocampal slices. Neurosteroids are involved in this LTP inhibition. We recently reported that the inhibitory effects of 60 mM ethanol are blocked by 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that acetaldehyde locally generated within the hippocampus participates in LTP inhibition. AIM We investigated whether acetaldehyde generated by ethanol metabolism contributes to neurosteroidogenesis and LTP inhibition. RESULTS Like 60 mM ethanol, we found that exogenous acetaldehyde enhanced neurosteroid immunostaining in CA1 pyramidal neurons, and that augmented neurosteroid immunostaining by high ethanol alone was blocked by 4MP but not by inhibitors of other ethanol metabolism pathways. The inhibitory effects of 60 mM ethanol on LTP were mimicked by a lower concentration of ethanol (20 mM) plus acetaldehyde (60 μM), although neither agent alone was effective at these concentrations, suggesting that 60 mM ethanol inhibits LTP via multiple actions, one of which involves acetaldehyde and the other of which requires only 20 mM ethanol. The effects of ethanol and acetaldehyde on neurosteroid staining and LTP were overcome by inhibition of neurosteroid synthesis and by blockade of N-methyl-D-aspartate receptors (NMDARs). CONCLUSION These observations indicate that acetaldehyde generated by local ethanol metabolism within the hippocampus serves as a signal for neurosteroid synthesis in pyramidal neurons, and participates in the synaptic dysfunction associated with severe alcohol intoxication.
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Affiliation(s)
- Kazuhiro Tokuda
- Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110
| | - Yukitoshi Izumi
- Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110
| | - Charles F Zorumski
- Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110
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Abstract
PURPOSE OF REVIEW This study reviews recent developments concerning the effects of alcohol on plasma triglycerides. The focus will be on population, intervention and metabolic studies with respect to alcohol and plasma triglycerides. RECENT FINDINGS Alcohol consumption and fat ingestion are closely associated and stimulated by each other via hypothalamic signals and by an elevated cephalic response. A J-shaped relationship between alcohol intake and plasma triglycerides has been described. A normal body weight, polyphenols in red wine and specific polymorphisms of the apolipoprotein A-V and apolipoprotein C-III genes may protect against alcohol-associated hypertriglyceridemia. In contrast, obesity exaggerates alcohol-associated hypertriglyceridemia and therefore the risk of pancreatitis. SUMMARY High alcohol intake remains harmful since it is associated with elevated plasma triglycerides, but also with cardiovascular disease, alcoholic fatty liver disease and the development of pancreatitis. Alcohol-induced hypertriglyceridemia is due to increased very-low-density lipoprotein secretion, impaired lipolysis and increased free fatty acid fluxes from adipose tissue to the liver. However, light to moderate alcohol consumption may be associated with decreased plasma triglycerides, probably determined by the type of alcoholic beverage consumed, genetic polymorphisms and lifestyle factors. Nevertheless, patients should be advised to reduce or stop alcohol consumption in case of hypertriglyceridemia.
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Affiliation(s)
- Boudewijn Klop
- Department of Internal Medicine, Sint Franciscus Gasthuis Rotterdam, the Netherlands
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Tokuda K, Izumi Y, Zorumski CF. Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus. Neurosci Lett 2013; 537:40-3. [PMID: 23352848 DOI: 10.1016/j.neulet.2013.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 12/31/2012] [Accepted: 01/07/2013] [Indexed: 11/27/2022]
Abstract
Consistent with the ability of severe alcohol intoxication to impair memory, high concentrations of ethanol (60mM) acutely inhibit long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To account for this, we hypothesized that local metabolism to acetaldehyde may contribute to the effects of high ethanol on synaptic function. However, sodium azide, a catalase inhibitor, and allyl sulfide, an inhibitor of cytochrome P450 2E1 (CYP2E1), failed to overcome LTP inhibition by 60mM ethanol. In contrast, LTP was successfully induced in the presence of ethanol plus 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that local metabolism via alcohol dehydrogenase contributes to synaptic effects. Furthermore, exogenously administered acetaldehyde overcame the effects of 4MP on LTP inhibition mediated by ethanol. These observations indicate that acetaldehyde generated by local metabolism within the hippocampus participates in the synaptic dysfunction associated with severe alcohol intoxication.
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Affiliation(s)
- Kazuhiro Tokuda
- Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
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Karim S, Liaskou E, Hadley S, Youster J, Faint J, Adams DH, Lalor PF. An in vitro model of human acute ethanol exposure that incorporates CXCR3- and CXCR4-dependent recruitment of immune cells. Toxicol Sci 2013; 132:131-41. [PMID: 23300006 DOI: 10.1093/toxsci/kfs337] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is one of the commonest causes of cirrhosis and liver failure in the developed world. Hepatic inflammation is the critical stage in progression of both ALD and non-ALD, but it remains difficult to study the underlying mechanisms in a human system, and current animal models do not fully recapitulate human liver disease. We developed a human tissue-based system to study lymphocyte recruitment in response to ethanol challenge. Precision-cut liver slices (PCLS) from human livers were incubated in culture, and hepatic function was determined by albumin production, 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide assay, glucose uptake responses, and morphometric assessment. Responses of tissue and lymphocytes to ethanol exposure were determined by PCR, flow cytometry, histology, and lymphocyte infiltration assays. Human PCLS demonstrated appropriate upregulation of CYP2E1, ADH1α, and ADH3 in response to ethanol treatment. Ethanol also induced expression of endothelial VCAM-1 and ICAM-1, production of sICAM-1 and CXCL8, and the chemokine receptors CXCR3 and CXCR4 on CD4 and CD8 lymphocytes. CXCR3- and CXCR4-dependent migration of lymphocytes into the tissue increased significantly in response to treatment with ethanol. We have demonstrated that ethanol increases chemokine receptor expression and lymphocyte recruitment into human liver tissue, suggesting that it may operate directly to promote hepatitis in ALD. The physiological and pathophysiological responses of the PCLS to ethanol in vitro highlight the potential of this assay for dissecting the molecular mechanisms underlying human liver inflammation and as a screening tool for novel therapeutics.
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Affiliation(s)
- Sumera Karim
- Institute of Biomedical Research, University of Birmingham, Birmingham, UK
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CYP2E1-catalyzed alcohol metabolism: role of oxidant generation in interferon signaling, antigen presentation and autophagy. Subcell Biochem 2013; 67:177-97. [PMID: 23400922 DOI: 10.1007/978-94-007-5881-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cytochrome P450 2E1 (CYP2E1) is one of two major enzymes that catalyze ethanol oxidation in the liver. CYP2E1 is also unique because it is inducible, as its hepatic content rises after continuous (chronic) ethanol administration, thereby accelerating the rate of ethanol metabolism and affording greater tolerance to heavy alcohol consumption. However, the broad substrate specificity of CYP2E1 and its capacity to generate free radicals from alcohol and other hepatotoxins, places CYP2E1 as a central focus of not only liver toxicity, but also as an enzyme that regulates cytokine signaling, antigen presentation, and macromolecular degradation, all of which are crucial to liver cell function and viability. Here, we describe our own and other published work relevant to the importance of CYP2E1-catalyzed ethanol oxidation and how this catalysis affects the aforementioned cellular processes to produce liver injury.
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Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse. Int J Hepatol 2012; 2012:408190. [PMID: 22164338 PMCID: PMC3227458 DOI: 10.1155/2012/408190] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 08/23/2011] [Indexed: 11/18/2022] Open
Abstract
ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose) showed a concave increase with an increase in ethanol dose, inversely correlating with β. CL(T) (dose/AUC) linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.). When ADH-1 activity was calculated by multiplying ADH-1 content by its V(max)/mg (4.0) and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with β. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3.
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