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Niemelä O, Bloigu A, Bloigu R, Aalto M, Laatikainen T. Associations between Liver Enzymes, Lifestyle Risk Factors and Pre-Existing Medical Conditions in a Population-Based Cross-Sectional Sample. J Clin Med 2023; 12:4276. [PMID: 37445311 DOI: 10.3390/jcm12134276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/20/2023] [Accepted: 06/24/2023] [Indexed: 07/15/2023] Open
Abstract
While alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) enzymes are commonly used indicators of liver dysfunction recent studies have suggested that these may also serve as predictive biomarkers in the assessment of extrahepatic morbidity. In order to shed further light on the interactions between serum liver enzyme abnormalities, factors of lifestyle and health status we examined ALT and GGT activities in a population-based sample of 8743 adult individuals (4048 men, 4695 women from the National FINRISK 2002 Study, mean age 48.1 ± 13.1 years) with different levels of alcohol drinking, smoking, physical activity, body weight and the presence or absence of various pre-existing medical conditions. The assessments also included laboratory tests for inflammation, lipid status and fatty liver index (FLI), a proxy for fatty liver. The prevalence of ALT and GGT abnormalities were significantly influenced by alcohol use (ALT: p < 0.0005 for men; GGT: p <0.0005 for both genders), smoking (GGT: p <0.0005 for men, p =0.002 for women), adiposity (p < 0.0005 for all comparisons), physical inactivity (GGT: p <0.0005; ALT: p <0.0005 for men, p <0.05 for women) and coffee consumption (p <0.0005 for GGT in both genders; p <0.001 for ALT in men). The total sum of lifestyle risk factor scores (LRFS) influenced the occurrence of liver enzyme abnormalities in a rather linear manner. Significantly higher LRFS were observed in the subgroups of individuals with pre-existing medical conditions when compared with those having no morbidities (p <0.0005). In logistic regression analyses adjusted for the lifestyle factors, both ALT and GGT associated significantly with fatty liver, diabetes and hypertension. GGT levels also associated with coronary heart disease, angina pectoris, cardiac insufficiency, cerebrovascular disease, asthma and depression. Combinations of abnormal ALT and GGT activities significantly increased the odds for hypertension coinciding with abnormalities in biomarkers of inflammation, lipid status and FLI. The data indicates that ALT and GGT activities readily respond to unfavorable factors of lifestyle associating also with a wide array of pre-existing medical conditions. The data supports close links between both hepatic and extrahepatic morbidities and lifestyle risk factors and may open new insights on a more comprehensive use of liver enzymes in predictive algorithms for assessing mechanistically anchored disease conditions.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and Tampere University, 60220 Seinäjoki, Finland
| | - Aini Bloigu
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, 90014 Oulu, Finland
| | - Risto Bloigu
- Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, 90014 Oulu, Finland
| | - Mauri Aalto
- Department of Psychiatry, Seinäjoki Central Hospital and Tampere University, 33100 Tampere, Finland
| | - Tiina Laatikainen
- Department of Public Health and Social Welfare, Finnish Institute for Health and Welfare (THL), 00271 Helsinki, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland
- Joint Municipal Authority for North Karelia Social and Health Services, 80210 Joensuu, Finland
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Abstract
The medical disorders of alcoholism rank among the leading public health problems worldwide and the need for predictive and prognostic risk markers for assessing alcohol use disorders (AUD) has been widely acknowledged. Early-phase detection of problem drinking and associated tissue toxicity are important prerequisites for timely initiations of appropriate treatments and improving patient's committing to the objective of reducing drinking. Recent advances in clinical chemistry have provided novel approaches for a specific detection of heavy drinking through assays of unique ethanol metabolites, phosphatidylethanol (PEth) or ethyl glucuronide (EtG). Carbohydrate-deficient transferrin (CDT) measurements can be used to indicate severe alcohol problems. Hazardous drinking frequently manifests as heavy episodic drinking or in combinations with other unfavorable lifestyle factors, such as smoking, physical inactivity, poor diet or adiposity, which aggravate the metabolic consequences of alcohol intake in a supra-additive manner. Such interactions are also reflected in multiple disease outcomes and distinct abnormalities in biomarkers of liver function, inflammation and oxidative stress. Use of predictive biomarkers either alone or as part of specifically designed biological algorithms helps to predict both hepatic and extrahepatic morbidity in individuals with such risk factors. Novel approaches for assessing progression of fibrosis, a major determinant of prognosis in AUD, have also been made available. Predictive algorithms based on the combined use of biomarkers and clinical observations may prove to have a major impact on clinical decisions to detect AUD in early pre-symptomatic stages, stratify patients according to their substantially different disease risks and predict individual responses to treatment.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and Tampere University, Seinäjoki, Finland.
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Wang H, Li L, Zhang S. Non-linear relationship between gamma-glutamyl transferase and type 2 diabetes mellitus risk: secondary analysis of a prospective cohort study. J Int Med Res 2021; 48:300060520937911. [PMID: 32662704 PMCID: PMC7361500 DOI: 10.1177/0300060520937911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE To investigate the association between gamma-glutamyl transferase (GGT) and type 2 diabetes mellitus (T2DM) risk. METHODS This was a secondary analysis based on a publicly available DRYAD dataset that included 15 444 study participants that received medical examinations at a single centre in Japan between 2004 and 2015. Crude, minimally-adjusted and fully-adjusted regression models were used to evaluate the relationship between GGT levels and T2DM risk. RESULTS The study participants (mean ± SD age of 43.72 ± 8.90 years; 8415 of 15 444 [54.49%] were male) were followed-up for a median of 1968 days (5.39 years). After adjusting for potential covariates, a non-linear relationship between the baseline GGT level and T2DM incidence was observed. The inflection point for T2DM risk was 10 IU/l GGT; below this point, the T2DM incidence increased by 1.18-fold per unit change in GGT. Above this point, the association between GGT and the incidence rate of T2DM became nonsignificant. CONCLUSION Baseline GGT exhibited a non-linear association with T2DM incidence. Elevated GGT levels should be incorporated into routine screening for individuals at high risk of T2DM, allowing for early intervention targeting GGT to potentially reduce T2DM-related morbidity.
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Affiliation(s)
- Hao Wang
- Department of Cardiology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan Province, China
| | - Lixia Li
- Department of Cardiology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan Province, China
| | - Shouyan Zhang
- Department of Cardiology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan Province, China
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Liver enzymes in alcohol consumers with or without binge drinking. Alcohol 2019; 78:13-19. [PMID: 30890357 DOI: 10.1016/j.alcohol.2019.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND While alcohol use is linked with a wide variety of health problems, the question of whether differences in drinking patterns could yield different outcomes has remained unclear. PATIENTS AND METHODS We measured liver enzymes (ALT, GGT) from alcohol consumers with or without binge drinking from a population-based sample in Finland, where binge-type drinking is common. Data on alcohol use, diet, body weight, lifestyle (smoking, coffee consumption, physical activity), and health status were collected from 19225 subjects (9492 men, 9733 women), aged 25-74 years. The participants were subsequently classified to subgroups, both according to the frequencies of binge drinking and the amounts of regular alcohol intake (low-, medium-, and high-risk drinking). RESULTS The quantity of regular alcohol use was roughly linearly related with GGT and ALT activities. ANOVA analyses of the trends according to the frequency of binge drinking showed a significant GGT increase in both men (p < 0.0005) and women (p < 0.0005), and a significant increase of ALT in men (p < 0.0005). In those with low-risk overall consumption, markedly higher GGT (p < 0.0005) and ALT (p < 0.0005) occurred in those with binge drinking more than once a month, compared with those with no such occasions. Binge drinking occurring ≤1/month also resulted in higher GGT (p < 0.0005) and ALT (p < 0.05) activities. CONCLUSIONS These results emphasize possible adverse consequences of binge drinking on hepatic function even in those with low-risk overall consumption. The pattern of drinking should be more systematically implicated in clinical recommendations for drinking reduction.
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Archer M, Kampman O, Bloigu A, Bloigu R, Luoto K, Kultti J, Hämäläinen M, Moilanen E, Leinonen E, Niemelä O. Assessment of alcohol consumption in depression follow-up using self-reports and blood measures including inflammatory biomarkers. Alcohol Alcohol 2019; 54:243-250. [PMID: 30809628 DOI: 10.1093/alcalc/agz002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/21/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Abstract
AIMS Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.
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Affiliation(s)
- Mari Archer
- University of Tampere, Faculty of Medicine and Life Sciences, Tampere University Hospital, Department of Psychiatry, University of Tampere, Finland
| | - Olli Kampman
- University of Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Finland.,Seinäjoki Central Hospital, Department of Psychiatry, Seinäjoki, Finland
| | - Aini Bloigu
- Medical Informatics and Statistics Research Group, University of Oulu, Finland
| | - Risto Bloigu
- Medical Informatics and Statistics Research Group, University of Oulu, Finland
| | - Kaisa Luoto
- University of Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Finland.,Seinäjoki Central Hospital, Department of Psychiatry, Seinäjoki, Finland
| | - Johanna Kultti
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland
| | - Mari Hämäläinen
- The Immunopharmacology Research Group, University of Tampere, Faculty of Medicine and Life Sciences and Tampere University Hospital, University of Tampere, Finland
| | - Eeva Moilanen
- The Immunopharmacology Research Group, University of Tampere, Faculty of Medicine and Life Sciences and Tampere University Hospital, University of Tampere, Finland
| | - Esa Leinonen
- University of Tampere, Faculty of Medicine and Life Sciences, Tampere University Hospital, Department of Psychiatry, University of Tampere, Finland
| | - Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland
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Where should the safe limits of alcohol consumption stand in light of liver enzyme abnormalities in alcohol consumers? PLoS One 2017; 12:e0188574. [PMID: 29206836 PMCID: PMC5716536 DOI: 10.1371/journal.pone.0188574] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 11/09/2017] [Indexed: 12/12/2022] Open
Abstract
Objectives To estimate the prevalence and risk factors for abnormal liver enzymes in a large age- and gender stratified population-based sample of apparently healthy individuals with or without alcohol consumption and other health-related risk factors (adiposity, physical inactivity, smoking). Methods Data on alcohol use, smoking, diet and physical activity were recorded using structured questionnaires from 13,976 subjects (6513 men, 7463 women, aged 25–74 years) in the national FINRISK studies. Alcohol data was used to categorize the participants into abstainers, light drinkers, moderate drinkers and heavy drinkers. Serum gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) activities were measured using standard kinetic methods. Results Male light drinkers, moderate drinkers and heavy drinkers showed significantly higher relative risks of abnormal GGT than abstainers: 1.37 (95% confidence interval 1.11 to 1.71, p < 0.01), 2.72 (2.08 to 3.56, p < 0.0005), and 6.10 (4.55 to 7.17, p < 0.0005), respectively. Corresponding values for women were 1.22 (0.99 to 1.51, p = 0.065), 1.90 (1.44 to 2.51, p < 0.0005), and 5.91 (3.80 to 9.17, p < 0.0005). Estimated threshold doses for a significant GGT elevation was 14 standard weekly alcohol doses for men and 7 for women. Excess body weight and age over 40 years modulated the thresholds towards smaller quantities of alcohol. The risk of abnormal GGT was also significantly influenced by physical inactivity and smoking. The relative risks of abnormal ALT activities were increased in male heavy drinkers, especially in those presenting with adiposity and sedentary lifestyle. Conclusions Alcohol use markedly increases the risk for abnormal liver enzyme activities in those presenting with age over 40 years, obesity, smoking or sedentary lifestyle. The data should be considered in public health recommendations and in the definitions of safe limits of alcohol use.
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Niemelä O, Niemelä S, Ritvanen A, Gissler M, Bloigu A, Vääräsmäki M, Kajantie E, Werler MM, Surcel HM. Assays of Gamma-Glutamyl Transferase and Carbohydrate-Deficient Transferrin Combination from Maternal Serum Improve the Detection of Prenatal Alcohol Exposure. Alcohol Clin Exp Res 2016; 40:2385-2393. [PMID: 27650665 DOI: 10.1111/acer.13207] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/02/2016] [Indexed: 12/01/2022]
Abstract
BACKGROUND Alcohol use during pregnancy leads to detrimental effects on fetal development. As self-reports by mothers are known to be unreliable for assessing prenatal alcohol exposure, there is a need for sensitive and specific biomarkers for identifying those at risk for alcohol-affected offspring. METHODS We measured serum gamma-glutamyl transferase (GGT), carbohydrate-deficient transferrin (CDT), a mathematically formulated combination of GGT and CDT (GGT-CDT), and ethylglucuronide (EtG) concentrations from 1,936 mothers with a positive (n = 480) or negative (n = 1,456) history of alcohol use at the time of pregnancy. The material included 385 alcohol-abusing mothers who subsequently gave birth to children with fetal alcohol syndrome (FAS) and 1,551 mothers without FAS children including 95 women who reported a median of 1.0 standard drinks of alcohol per day during pregnancy and 1,456 nondrinking controls. Among those without FAS outcome, there were 405 mothers with gestational diabetes mellitus (GDM) and 745 mothers representing lifelong abstainers. RESULTS Mothers of FAS children had higher mean GGT, CDT, GGT-CDT, and EtG levels than abstainers (p < 0.001 for all comparisons) or mothers reporting some alcohol consumption but whose children were not diagnosed with FAS (p < 0.001 for all comparisons). In receiver operating characteristic analyses using cutoffs based on abstainers, the area under the curves (AUCs) for GGT-CDT (0.873) were higher than those of GGT (0.824), CDT (0.776), or EtG (0.584) for differentiating the mothers of FAS children and abstainers. Unlike CDT, this combination marker also differed significantly between drinking mothers without FAS outcome and abstainers (AUC = 0.730, p < 0.001). In comparisons adjusted for GDM and body mass index, the group of mothers who had reported a median of 1.0 standard drinks of alcohol per day during pregnancy also differed from the group reporting no current alcohol intake in GGT (p < 0.02) and GGT-CDT (p < 0.01) levels. CONCLUSIONS Combination of GGT and CDT improves the identification of prenatal alcohol exposure and associated high-risk pregnancies. A more systematic use of biomarkers may help intervention efforts to prevent alcohol-induced adverse effects on fetal development.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, University of Tampere, Seinäjoki, Finland.
| | - Solja Niemelä
- Research Unit of Clinical Neuroscience, Faculty of Medicine, University of Oulu, Oulu, Finland.,Department of Psychiatry, Lapland Hospital District, Rovaniemi, Finland
| | - Annukka Ritvanen
- Information Services Department, Finnish Register of Congenital Malformations, National Institute for Health and Welfare, Helsinki, Finland
| | - Mika Gissler
- Information Services Department, National Institute for Health and Welfare, Helsinki, Finland.,Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
| | - Aini Bloigu
- The Impact Assessment Unit, National Institute of Health and Welfare, Oulu, Finland
| | - Marja Vääräsmäki
- The Children, Adolescents and Families Unit, National Institute for Health and Welfare, Oulu, Finland.,PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Eero Kajantie
- PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.,Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki and Oulu, Finland.,Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Martha M Werler
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
| | - Heljä-Marja Surcel
- The Impact Assessment Unit, National Institute of Health and Welfare, Oulu, Finland
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Niemelä O. Biomarker-Based Approaches for Assessing Alcohol Use Disorders. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:166. [PMID: 26828506 PMCID: PMC4772186 DOI: 10.3390/ijerph13020166] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/14/2016] [Accepted: 01/20/2016] [Indexed: 12/11/2022]
Abstract
Although alcohol use disorders rank among the leading public health problems worldwide, hazardous drinking practices and associated morbidity continue to remain underdiagnosed. It is postulated here that a more systematic use of biomarkers improves the detection of the specific role of alcohol abuse behind poor health. Interventions should be initiated by obtaining information on the actual amounts of recent alcohol consumption through questionnaires and measurements of ethanol and its specific metabolites, such as ethyl glucuronide. Carbohydrate-deficient transferrin is a valuable tool for assessing chronic heavy drinking. Activities of common liver enzymes can be used for screening ethanol-induced liver dysfunction and to provide information on the risk of co-morbidities including insulin resistance, metabolic syndrome and vascular diseases. Conventional biomarkers supplemented with indices of immune activation and fibrogenesis can help to assess the severity and prognosis of ethanol-induced tissue damage. Many ethanol-sensitive biomarkers respond to the status of oxidative stress, and their levels are modulated by factors of life style, including weight gain, physical exercise or coffee consumption in an age- and gender-dependent manner. Therefore, further attention should be paid to defining safe limits of ethanol intake in various demographic categories and establishing common reference intervals for biomarkers of alcohol use disorders.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki 60220, Finland.
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Danielsson J, Kangastupa P, Laatikainen T, Aalto M, Niemelä O. Impacts of common factors of life style on serum liver enzymes. World J Gastroenterol 2014; 20:11743-11752. [PMID: 25206278 PMCID: PMC4155364 DOI: 10.3748/wjg.v20.i33.11743] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impacts of gender, age and factors of life style (alcohol, overweight, coffee and smoking) on serum liver enzymes.
METHODS: Serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were measured from 6269 apparently healthy individuals (2851 men, 3418 women, mean age 45 ± 12 years, range 25-74 years) in a national cross-sectional health survey. All subjects underwent detailed clinical examinations and interviews including the amount and pattern of alcohol use, coffee consumption and smoking habits.
RESULTS: In this population with a mean ± SD alcohol consumption of 65 ± 105 g/wk and body mass index (BMI) of 26.1 ± 4.3 kg/m2, both ALT and GGT were significantly influenced by alcohol use (P < 0.001) and BMI (P < 0.001), whereas smoking increased only GGT (P < 0.001). A significant effect of age on ALT was seen in men (P < 0.001) whereas not in women. Significant two-factor interactions of alcohol use in men were observed with age (ALT: P < 0.01; GGT: P < 0.001) and BMI (GGT: P < 0.05). For ALT, a significant interaction also occurred between BMI and age (P < 0.005). In contrast, women showed significant interactions of alcohol use with BMI (GGT: P < 0.05), smoking (GGT: P < 0.001), and coffee consumption (GGT: P < 0.001).
CONCLUSION: Life-style associated changes in liver enzymes may reflect health risks, which should be considered in the definition of normal limits for liver enzymes.
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Abstract
Up to 30% of all hospital admissions and health-care costs may be attributable to alcohol abuse. Ethanol, its oxidative metabolites, acetaldehyde and ROS (reactive oxygen species), non-oxidative metabolites of alcohol [e.g. FAEEs (fatty acid ethyl esters)] and the ethanol-water competition mechanism are all involved in the deregulation of glycoconjugate (glycoprotein, glycolipid and proteoglycan) metabolic processes including biosynthesis, modification, transport, secretion, elimination and catabolism. An increasing number of new alcohol biomarkers that are the result of alcohol-induced glycoconjugate metabolic errors have appeared in the literature. Glycoconjugate-related alcohol markers are involved in, or are a product of, altered glycoconjugate metabolism, e.g. CDT (carbohydrate-deficient transferrin), SA (sialic acid), plasma SIJ (SA index of apolipoprotein J), CETP (cholesteryl ester transfer protein), β-HEX (β-hexosaminidase), dolichol, EtG (ethyl glucuronide) etc. Laboratory tests based on changes in glycoconjugate metabolism are useful in settings where the co-operativeness of the patient is impaired (e.g. driving while intoxicated) or when a history of alcohol use is not available (e.g. after trauma). In clinical practice, glycoconjugate markers of alcohol use/abuse let us distinguish alcoholic from non-alcoholic tissue damage, having important implications for the treatment and management of diseases.
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Alatalo PI, Koivisto HM, Hietala JP, Bloigu RS, Niemelä OJ. Gender-dependent impacts of body mass index and moderate alcohol consumption on serum uric acid--an index of oxidant stress status? Free Radic Biol Med 2009; 46:1233-8. [PMID: 19439211 DOI: 10.1016/j.freeradbiomed.2009.02.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Revised: 01/06/2009] [Accepted: 02/05/2009] [Indexed: 01/02/2023]
Abstract
Uric acid seems to be causally involved in a variety of medical disorders involving oxidative stress. Although alcohol abuse and obesity are known to increase serum uric acid, the interactions between moderate drinking, adiposity, and uric acid metabolism have remained poorly understood. We examined serum uric acid concentrations from 2062 apparently healthy volunteers (970 men, 1092 women) reporting either no alcohol (abstainers) or <40 g of ethanol consumption per day (moderate drinkers). The study population was further classified according to BMI as follows: <19 (underweight), 19-25 (normal weight), 25-30 (overweight), and >30 (obese). Serum uric acid concentrations in male moderate drinkers were significantly higher, and in females they were lower, than in the corresponding groups of abstainers. In the BMI-based subgroups, the highest concentrations were found in those who were overweight or obese. Significant two-factor interactions occurred between gender and drinking status (p<0.001) and between gender and BMI (p<0.02). Serum uric acid also correlated with indices of hepatocellular health (GGT, ALT, AST). The data indicate distinct gender-dependent impacts of alcohol consumption and BMI on serum uric acid. These findings should be applicable to the assessment of oxidative stress status and associated morbidity in alcohol consumers and individuals with excess body weight.
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Affiliation(s)
- Päivikki I Alatalo
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, and University of Tampere, Seinäjoki, Finland
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12
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Alatalo PI, Koivisto HM, Hietala JP, Puukka KS, Bloigu R, Niemelä OJ. Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. Am J Clin Nutr 2008; 88:1097-103. [PMID: 18842799 DOI: 10.1093/ajcn/88.4.1097] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although both ethanol consumption and overweight alter the activities of hepatic enzymes in circulation, the differentiation of an alcohol or nonalcohol basis for such changes remains problematic. The magnitude of alterations occurring among moderate drinkers has remained obscure. OBJECTIVE We examined the links between moderate ethanol consumption, body mass index (BMI; in kg/m(2)), and liver enzymes. DESIGN Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were recorded from 2,164 apparently healthy participants (1,028 men, 1,136 women) reporting either no alcohol (abstainers) or <40 g ethanol consumption per day (moderate drinkers). The study population was further classified according to BMI as follows: <19 (underweight), > or =19 and <25 (normal weight), > or =25 and <30 (overweight), and > or =30 (obese). RESULTS Serum ALT (P < 0.05) and GGT (P < 0.001) but not AST (P = 0.805) activities in moderate drinkers were higher than those in abstainers. For all enzymes, a significant main effect was observed of increasing BMI, which was more striking in moderate drinkers than in abstainers. Tests of between-subjects effects indicated significant interactions with sex and drinking status, although not with sex and BMI. CONCLUSIONS The effect of moderate alcohol consumption on liver enzymes increases with increasing BMI. These findings should be considered in the clinical assessment of overweight alcohol consumers and in the definition of normal ranges for liver enzymes. These results may also help to develop new approaches for examining patients with fatty liver induced by either ethanol or adiposity.
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Affiliation(s)
- Päivikki I Alatalo
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland
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Puukka K, Hietala J, Koivisto H, Anttila P, Bloigu R, Niemelä O. Obesity and the clinical use of serum GGT activity as a marker of heavy drinking. Scandinavian Journal of Clinical and Laboratory Investigation 2007; 67:480-8. [PMID: 17763184 DOI: 10.1080/00365510601146035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Gamma-glutamyl transferase (GGT) is a widely used clinical marker of alcohol abuse. However, although obesity may also elevate serum GGT activities, the effects of overweight on the interpretation of GGT testing have remained poorly defined. MATERIAL AND METHODS GGT activities from 1147 moderate drinkers and 449 abstainers who were classified according to body mass index (BMI) were compared with those of 208 heavy drinkers admitted for detoxification. RESULTS GGT upper normal limits, defined based on normal weight abstainers (men 53 U/L; women 45 U/L) were lower than those based on moderate drinkers (men 68 U/L; women 50 U/L). The relative increases in GGT activities in male moderate drinkers with overweight (54%) or obesity (125%) exceeded the corresponding changes found in women (25% and 75%, respectively). The BMI-dependent variation on the sensitivity of GGT for correctly classifying heavy drinkers ranged from 29% to 67%. The rates of false-positive values in the subgroups from low to high BMI varied from 0% to 27%, respectively. CONCLUSIONS The data indicate that the diagnostic value of serum GGT testing could be improved by using reference data derived from databases of abstainers with normal weight or BMI-based categorization of reference ranges.
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Affiliation(s)
- K Puukka
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland
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Niemelä O. Biomarkers in alcoholism. Clin Chim Acta 2006; 377:39-49. [PMID: 17045579 DOI: 10.1016/j.cca.2006.08.035] [Citation(s) in RCA: 162] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2006] [Revised: 08/28/2006] [Accepted: 08/30/2006] [Indexed: 12/18/2022]
Abstract
Alcoholism ranks as one of the main current threats to the health and safety of people in most Western countries. Therefore, a high priority should be given to aims at reducing its prevalence through more effective diagnosis and early intervention. The need for objective methods for revealing alcohol abuse in its early phase has also been widely acknowledged. It is postulated here that the diagnosis of alcohol use disorders could be markedly improved by a more systematic use of specific questionnaires and laboratory tests, including blood ethanol, serum gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), and mean corpuscular volume of erythrocytes (MCV). Recent research has provided new insights into the relationships between ethanol intake, biomarkers, and factors affecting their diagnostic validation, including gender, age, and the effects of moderate drinking and obesity. It appears that the concept of reference intervals for several ethanol-sensitive parameters in laboratory medicine needs to be revisited. CDT is currently the most specific marker of alcohol abuse, and when combined with GGT using a mathematically formulated equation a high sensitivity is reached without loss of assay specificity. Possible new biomarkers include minor ethanol metabolites (protein-acetaldehyde condensates and associated autoimmune responses, ethylglucuronide, and phosphatidylethanolamine), 5-hydroxytryptophol, and genetic markers although so far their routine applications have been limited.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, FIN-60220 Seinäjoki, Finland.
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15
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Puukka K, Hietala J, Koivisto H, Anttila P, Bloigu R, Niemelä O. Age-related changes on serum ggt activity and the assessment of ethanol intake. Alcohol Alcohol 2006; 41:522-7. [PMID: 16855003 DOI: 10.1093/alcalc/agl052] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIMS Gamma-glutamyl transferase (GGT) is a commonly used marker of ethanol abuse. However, although increasing age has also been suggested to elevate serum GGT activities, the magnitude of such effects on GGT in the assessment of ethanol intake have remained poorly defined. METHODS GGT activities from 208 heavy drinkers were compared with those from a reference population including 1330 moderate drinkers and 1160 abstainers, who were further classified to following age intervals: 18-30, 30-50, 50-70, and >70 years. RESULTS GGT activities increased with increasing age until after 70 years decreasing values were noted in male abstainers. The heavy drinkers belonging to age groups 18-30, 30-50, and 50-70 years showed 2.7-, 8.0-, and 6.9-fold higher mean GGT activities than those in the corresponding groups of abstainers, respectively. The values in the group of moderate drinkers also exceeded those of abstainers in all age groups of men, whereas in women the difference was significant only among those aged 18-30 years. CONCLUSIONS The data indicate that GGT activities respond to ethanol intake in an age-dependent manner, which should be considered in the clinical use of GGT measurements for detecting alcohol use disorders.
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Affiliation(s)
- Katri Puukka
- Seinäjoki Central Hospital, Laboratory, FIN-60220 Seinäjoki, Finland
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16
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Puukka K, Hietala J, Koivisto H, Anttila P, Bloigu R, Niemelä O. Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase activity. Am J Clin Nutr 2006; 83:1351-4; quiz 1448-9. [PMID: 16789344 DOI: 10.1093/ajcn/83.6.1351] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Gamma-glutamyl transferase (GGT) is a widely used index of liver induction and a marker of alcohol overconsumption. Obesity has also been suggested to elevate serum GGT activities. OBJECTIVE The aim was to examine the links between moderate ethanol consumption, obesity, and GGT activities. DESIGN GGT values were recorded from 2490 persons (1184 men and 1306 women) who reported either no alcohol use (abstainers) or 1-40 g ethanol consumption per day (moderate drinkers). The study population was additionally classified according to body mass index (BMI; in kg/m2) as follows: < 19 (underweight), > or = 19 and < 25 (normal weight), > or = 25 and < 30 (overweight), and 30 (obese). RESULTS Significant main effects of sex (P < 0.0001), drinking habits (P < 0.01), and BMI (P < 0.001) on serum GGT activities were observed. The values were higher in the men than in the women and higher in those with higher BMIs. The highest activities were found to occur in persons with moderate drinking combined with overweight or obesity. A significant positive correlation between GGT and BMI (P < 0.0001) was observed, which was stronger for the men (r = 0.24) than for the women (r = 0.15, P < 0.05 for the difference between correlations). CONCLUSION The data indicate that serum GGT activities may respond to moderate drinking and overweight in an additive manner; this should be considered in the clinical use of GGT measurements and when defining normal GGT values in health care.
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Affiliation(s)
- Katri Puukka
- Department of Laboratory Medicine Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland
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17
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Chaïb S, Charrueau C, Neveux N, Coudray-Lucas C, Cynober L, De Bandt JP. Isolated perfused liver model: the rat and guinea pig compared. Nutrition 2004; 20:458-64. [PMID: 15105034 DOI: 10.1016/j.nut.2004.01.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Although the rat is the most commonly used species for the study of hepatic metabolism, the physiology of the guinea pig is closer to human physiology. We compared the model of isolated perfused guinea pig liver with the classic model of isolated perfused rat liver, especially with respect to amino acid metabolism. METHODS After validation of an anesthetic mixture of ketamine, diazepam, and xylazine for the guinea pig, isolated perfused livers were harvested for both species. Three groups of animals were compared for the study of liver metabolic fluxes: 6-wk-old male Sprague-Dawley rats (R; 230 +/- 10 g, n = 5), young male Hartley guinea pigs (YG; 223 +/- 8 g, n = 6) matched to rats by liver weight, and adult male Hartley guinea pigs (AG; 389 +/- 5 g, n = 6) matched to rats by age. Results (mean +/- standard error of the mean) were compared by analysis of variance and Newman-Keuls tests. RESULTS Both models displayed a satisfactory hepatic viability, but differences were noted, with higher portal flows (R: 3.1 +/- 0.3 versus YG: 4.5 +/- 0.3 and AG: 4.2 +/- 0.3 mL. min(-1). g(-1); P < 0.05, YG and AG versus R) and bile flows (R: 0.34 +/- 0.01 versus YG: 2.38 +/- 0.22 versus AG: 3.17 +/- 0.28 microL. min(-1). g(-1); P < 0.05, YG and AG versus R, and YG versus AG) and higher amino acid fluxes (P < 0.05) leading to greater nitrogen uptake (P < 0.05) in guinea pigs. We performed a second set of experiments to evaluate the influence of anesthesia and portal flow on this last parameter. In these experiments, rats were anesthetized with ketamine, diazepam, and xylazine and guinea pig livers were perfused at rat blood flow. Apart from a 50% anesthesia-related mortality for rats, bile flow and metabolic parameters were only slightly modified. However, some amino acid fluxes were statistically different (aspartate, serine, and histidine; P < 0.05), as confirmed by a higher transfer constant. CONCLUSION Our results indicate that the isolated perfused guinea pig liver is a suitable model for the study of hepatic metabolism.
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Affiliation(s)
- Samira Chaïb
- Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Laboratoire de Biochimie A, Hôpital Hôtel-Dieu AP-HP, Paris, France
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Yokoyama H, Moriya S, Homma Y, Ogawa T. Association between gamma-glutamyl transpeptidase activity and status of disorders constituting insulin resistance syndrome. Alcohol Clin Exp Res 2003; 27:22S-25S. [PMID: 12960502 DOI: 10.1097/01.alc.0000078608.22813.d9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Serum gamma-glutamyl transferase (gamma GTP) activity is a well-established marker of alcohol consumption. However, recently, a correlation between serum gamma GTP activity and insulin resistance status has been demonstrated. METHODS To determine whether serum gamma GTP activity could be associated with the status of various disorders caused by increased insulin resistance levels, namely, insulin resistance syndrome, a cross-sectional study for 11,884 Japanese men was performed. They were divided into three groups by their age, and associations between gamma GTP and various indexes of insulin resistance syndrome were studied by multiple logistic regression analysis in which subjects' drinking styles were corrected for in each age bracket. RESULTS Consuming ethanol more than 40 g/day, body mass index more than 25.9 kg/m2, and triglyceride levels more than 150 mg/dl were significant risk factors accounting for increased gamma GTP activity (more than 78 IU/liters) irrespective of age. In addition, when subjects of 40 to 59 years old were selectively studied, hypertension, hypercholesteremia, hyperuricemia, and increased glycohemoglobin A1C levels were also significant risk factors for increased gamma GTP activity. CONCLUSIONS There are significant associations between gamma GTP and the status of insulin resistance syndrome. In addition to excessive alcohol consumption, the status of insulin resistance syndrome could affect subjects' gamma GTP activities.
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Abstract
Serum gamma-glutamyl transferase (GGT) has been widely used as an index of liver dysfunction and marker of alcohol intake. The last few years have seen improvements in these areas and advances in understanding of its physiological role in counteracting oxidative stress by breaking down extracellular glutathione and making its component amino acids available to the cells. Conditions that increase serum GGT, such as obstructive liver disease, high alcohol consumption, and use of enzyme-inducing drugs, lead to increased free radical production and the threat of glutathione depletion. However, the products of the GGT reaction may themselves lead to increased free radical production, particularly in the presence of iron. There have also been important advances in the definition of the associations between serum GGT and risk of coronary heart disease, Type 2 diabetes, and stroke. People with high serum GGT have higher mortality, partly because of the association between GGT and other risk factors and partly because GGT is an independent predictor of risk. This review aims to summarize the knowledge about GGT's clinical applications, to present information on its physiological roles, consider the results of epidemiological studies, and assess how far these separate areas can be combined into an integrated view.
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Affiliation(s)
- J B Whitfield
- Department of Clinical Biochemistry, Royal Prince Alfred Hospital, and University of Sydney, NSW, Australia.
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20
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Abstract
Boldine is a natural compound with well-established free radical scavenger and hepatoprotective properties. The further exploration of its actual therapeutic potential as an antioxidant is, however, partially limited by the absence of knowledge on its pharmacokinetics. In the present studies, we provide information on the in vitro and in vivo biological disposition of boldine. The addition of 200 microM boldine to an isolated rat hepatocyte suspension was followed by a time-dependent (0-60 min) disappearance of boldine from the extracellular medium. This decline was associated with an early (first 2 min) and swift accumulation (1600 microM) of boldine within the cells. Although the intracellular concentration of boldine diminished, boldine was always found to occur within the cells at concentrations substantially higher than those initially added to the preparation. Boldine was also concentration-dependently removed from the extracellular medium by isolated rat livers portally perfused with the antioxidant. In vivo studies, conducted in rats, revealed that following either its oral or its intravenous administration, plasma boldine concentrations declined rapidly and according to an apparently first order type of kinetics. After its oral administration (50 or 75 mg/kg), boldine was rapidly (within 30 min) absorbed and preferentially concentrated in the liver, with substantially lower concentrations being found in the brain and heart. Maximal hepatic concentrations of boldine were found to be equal to or greater than those needed to afford antioxidant and hepatoprotective effects in vitro.
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Affiliation(s)
- I Jiménez
- Laboratory of Lipids and Antioxidants, Nutrition and Food Technology Institute, University of Chile, Santiago, Chile
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21
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Relationship between liver gamma-glutamyltranspeptidase activity and glutathione content in chronic-malnourished pups of adolescent rats. Nutr Res 2000. [DOI: 10.1016/s0271-5317(99)00142-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Chikhi N, Holic N, Guellaen G, Laperche Y. Gamma-glutamyl transpeptidase gene organization and expression: a comparative analysis in rat, mouse, pig and human species. Comp Biochem Physiol B Biochem Mol Biol 1999; 122:367-80. [PMID: 10392451 DOI: 10.1016/s0305-0491(99)00013-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Gamma-glutamyl transpeptidase (GGT) is an enzyme located at the external surface of epithelial cells. It initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. GGT expression, highly sensitive to oxidative stress, is a part of the cell antioxidant defense mechanisms. We describe recent advances in GGT gene structure and expression knowledge and put emphasis on the complex transcriptional organization of that gene and its conservation among different species. GGT gene structure has been elucidated in rat and mouse where a single gene is transcribed from multiple promoters into several transcripts which finally yield a unique polypeptidic chain. Analysis of rat, mouse, human and pig cDNA and gene sequences reveals a large conservation of the transcriptional organization of that gene. This complex structure provides flexibility in GGT expression controlled at the promoter level, through multiple regulatory sites, and at RNA level by alternate 5' untranslated sequences which may create a diversity in the stability and translational efficiency of the different transcripts. In conclusion, transcription of the GGT gene from several promoters offers multiple DNA and RNA targets for various oxidative stimuli and contributes to a broad antioxidant cell defense through GGT induction and subsequent cysteine supply from extracellular glutathione.
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Affiliation(s)
- N Chikhi
- INSERM Unité 99, Université Paris XII, Hôpital Henri Mondor, Créteil, France
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De-Oliveira IM, Fujimori E, Pereira VG, De-Castro VD. DL-methionine supplementation of rice-and-bean diets affects gamma-glutamyltranspeptidase activity and glutathione content in livers of growing rats. Braz J Med Biol Res 1999; 32:483-8. [PMID: 10347814 DOI: 10.1590/s0100-879x1999000400017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Gamma-glutamyltranspeptidase (GGT-EC 2.3.2.2) activity and glutathione (GSH) content were measured in livers of female weanling Wistar rats (N = 5-18), submitted to rice-and-bean diets (13 and 6% w/w protein), both supplemented or not with DL-methionine (0.5 and 0.23 g/100 g dry diet, respectively). After 28 days, the rats on the rice-and-bean diets showed significantly higher levels (four times higher) of liver GGT activity and a concomitant 50% lower concentration of liver GSH in comparison with control groups feeding on casein. The addition of DL-methionine to rice-and-bean diets significantly increased the liver GSH content, which reached levels 50% higher than those found in animals on casein diets. The increase in GSH was accompanied by a decrease in liver GGT activity, which did not reach levels as low as those observed in the control groups. No significant correlation could be established between GGT and GSH changes under the present experimental conditions. Linear correlation analysis only revealed that in animals submitted to unsupplemented rice-and-bean diets GSH concentration was positively associated (P < 0.05) with weight gain, food intake and food efficiency. GGT, however, was negatively correlated (P < 0.05) with food intake only, and exclusively for supplemented rice-and-bean diets. The high levels of GGT activity observed in the present study for rats receiving a rice-and-bean mixture could be a result of the poor quality of these diets associated with their deficiency in sulfur amino acids. The results also suggest that diet supplementation with methionine could be important in the reduction of the deleterious effects of GSH depletion by restoring the intracellular concentration of this tripeptide.
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Affiliation(s)
- I M De-Oliveira
- Departamento de Enfermagem em Saúde Coletiva, Escola de Enfermagem, Universidade de São Paulo, Brasil.
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24
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Milne RW, Jensen RH, Larsen C, Evans AM, Nation RL. Comparison of the disposition of hepatically-generated morphine-3-glucuronide and morphine-6-glucuronide in isolated perfused liver from the guinea pig. Pharm Res 1997; 14:1014-8. [PMID: 9279882 DOI: 10.1023/a:1012145126847] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. METHODS Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 microM). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. RESULTS Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (+/-s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 +/- 1.5. A mean 33 +/- 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 +/- 11% and 9 +/- 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). CONCLUSIONS A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.
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Affiliation(s)
- R W Milne
- Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
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25
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Marinho HS, Baptista M, Pinto RE. Glutathione metabolism in hepatomous liver of rats treated with diethylnitrosamine. BIOCHIMICA ET BIOPHYSICA ACTA 1997; 1360:157-68. [PMID: 9128181 DOI: 10.1016/s0925-4439(96)00075-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Glutathione metabolism was studied in rat liver during diethylnitrosamine (DEN) carcinogenesis. Some studies were also made in foetal rat liver. Endogenous GSH and non-protein thiols concentrations are increased in DEN-treated rats when compared to non-treated rats but no differences were found in cysteine, total thiols and protein thiols concentration. In foetal liver GSH concentration is only 35% of that in DEN-treated rat liver. The activities of several enzymes involved in glutathione metabolism are changed in DEN-treated rats. gamma-Glutamyl transferase activity and cysteine formation from GSH by liver homogenates is increased sevenfold. gamma-Glutamylcysteine synthetase activity, initial rate of [35S]cysteine incorporation in gamma-glutamylcysteine and initial rate of GSH formation from [35S]cysteine are increased two-fold. Cytosolic GSH S-transferase activity is increased twofold in DEN-treated rats and so GSH S-conjugates concentration is probably also increased. In foetal rat liver gamma-glutamyl transferase activity is about the same but gamma-glutamylcysteine synthetase activity is only 10% of that in DEN-treated rat liver. The increased GSH concentration in DEN-treated rat liver is probably due to the simultaneous increase in the activities of gamma-glutamyl transferase and gamma-glutamylcysteine synthetase. Blood plasma total glutathione is increased 1.4 times in DEN-treated rats, but no differences are found in GSH hepatic arteriovenous gradient. This associated with the increased gamma-glutamyl transferase activity suggests that sinusoidal GSH efflux is increased in DEN-treated rats.
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Affiliation(s)
- H S Marinho
- Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
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Kaplowitz N, Fernández-Checa JC, Kannan R, Garcia-Ruiz C, Ookhtens M, Yi JR. GSH transporters: molecular characterization and role in GSH homeostasis. BIOLOGICAL CHEMISTRY HOPPE-SEYLER 1996; 377:267-73. [PMID: 8828817 DOI: 10.1515/bchm3.1996.377.5.267] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Considerable progress has been made in the last few years in the molecular identification and characterization of hepatic GSH transporter-associated polypeptides. We are now poised to determine their precise mechanisms of action and regulation at the transcriptional and post-translational level. It is also anticipated that molecular characterization of the mitochondrial GSH transporter and sodium GSH co-transporters will be accomplished in the near future. With this information, a more complete understanding of GSH/cysteine homeostasis can be achieved which can be applied to furthering the prevention and treatment of the diseases of oxidative stress, such as aging, HIV, cataract, atherosclerosis, cancer and alcoholic liver disease.
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Affiliation(s)
- N Kaplowitz
- USC Center for Liver Diseases, USC School of Medicine, Los Angeles, 90033-4581, USA
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Videla LA, Fernández V. Effect of thyroid hormone administration on the depletion of circulating glutathione in the isolated perfused rat liver and its relationship to basolateral gamma-glutamyltransferase activity. JOURNAL OF BIOCHEMICAL TOXICOLOGY 1995; 10:69-77. [PMID: 7562955 DOI: 10.1002/jbt.2570100203] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The influence of thyroid hormone administration on liver glutathione (GSH) extraction in the isolated perfused liver was studied in fed rats for a period of 1-7 days following a single dose of 0.1 mg 3,5,3'-triiodothyronine (T3)/kg. T3 treatment led to an early and transient calorigenic response, as well as an enhancement in liver GSH removal, reaching a maximal effect at 2 days after hormone administration, which was normalized in the 3- to 7-day period studied. Addition of the gamma-glutamyltransferase (gamma-GT) inhibitor DL-serineborate (4 mM) to the perfusate abolished the increase in the hepatic removal of GSH elicited by T3, and enhanced the sinusoidal concentration of GSH, studied at 2 days after hormone administration. These data support the role of hepatic basolateral gamma-GT ectoactivity in the depletion of portally added and liver-derived GSH as an adaptive response to recover GSH levels after reduction by T3-induced oxidative stress.
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Affiliation(s)
- L A Videla
- Departamento de Bioquimica, Facultad de Medicina, Universidad de Chile, Santiago
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Tamano T, Yoshida H, Kuronuma Y, Harada T. Role of renal gamma-glutamyltransferase activity in hepatic utilization of exogenous glutathione. J Gastroenterol 1995; 30:74-8. [PMID: 7719418 DOI: 10.1007/bf01211378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The importance of renal gamma-glutamyltransferase activity in the hepatic utilization of exogenous glutathione (GSH) was evaluated by injecting GSH (1.67 mmol/kg body wt) i.v. into bilaterally nephrectomized and sham-operated Sprague-Dawley rats in which endogenous hepatic GSH had been decreased (0.20 +/- 0.01 mumol/g liver vs 5.87 +/- 0.26 mumol/g liver in normal controls, mean +/- SD) by diethylmaleate (0.5 ml/kg body wt, i.p.). Hepatic GSH concentration 60 min after GSH administration was lower in the nephrectomized than in the sham-operated rats (0.87 +/- 0.25 mumol/g liver vs 3.08 +/- 0.81 mumol/g liver, P < 0.001), while plasma GSH concentration was higher in the former (4.61 +/- 1.07 mM vs 0.11 +/- 0.06 mM, P < 0.001). In rats with intact kidneys which had been given a gamma-glutamyltransferase inhibitor (acivicin, 25 mumol/kg body wt i.v.) prior to GSH administration, the hepatic GSH concentrations (1.11 +/- 0.49 mumol/g liver) were comparable to those obtained in the nephrectomized rats. When N-acetylcysteine (1.67 mmol/kg body wt, i.v.) was administered instead of GSH, the hepatic GSH concentrations were similar in nephrectomized and sham-operated rats (1.54 +/- 0.23 mumol/g liver vs 2.22 +/- 0.58 mumol/g liver, NS). The gamma-glutamyltransferase activity was much higher in the kidney than in the liver (4460 +/- 830 IU/kg body wt vs 14 +/- 7 IU/kg body wt). These results indicate that the kidney plays an essential role in the hepatic utilization of exogenous GSH through its high gamma-glutamyltransferase activity.
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Affiliation(s)
- T Tamano
- Second Department of Internal Medicine, Dokkyo University School of Medicine, Tochigi, Japan
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Pang KS. Acinar factors in drug processing: protein binding, futile cycling, and cosubstrate. Drug Metab Rev 1995; 27:325-68. [PMID: 7641582 DOI: 10.3109/03602539509029829] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- K S Pang
- Faculty of Pharmacy, University of Toronto, Canada
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Vendemiale G, Palmieri V, Palasciano G, Altomare E. Effect of glutathione administration on hepatic biliary and plasmatic glutathione levels in the rat. Scand J Gastroenterol 1994; 29:1034-8. [PMID: 7871370 DOI: 10.3109/00365529409094882] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Since the effect of exogenous glutathione (GSH) on overall hepatic GSH homeostasis is not known, the present study investigated the changes in the hepatic, biliary, and plasmatic GSH levels during GSH administration in intact rats. METHODS An exteriorized biliary-duodenal fistula was established, and GSH (1 mmol/kg over 2 h) or saline was administered intraperitoneally to rats with or without pretreatment with 5 mmol/kg L-serine borate, an inhibitor of gamma-glutamyltransferase (GGT). RESULTS Three hours after GSH administration, biliary GSH efflux and bile flow rose from 104.7 +/- 5.6 to 290.6 +/- 8.6 micrograms/ml bile and from 20.2 +/- 1.3 to 30.2 +/- 2.1 microliters/min, respectively; GSH-treated rats also showed increased liver (35%) and posthepatic vein plasma (68%) GSH concentrations compared with controls. By contrast, in rats pretreated with the GGT inhibitor GSH administration appeared to be devoid of any effect, except for a modest biliary GSH increase. CONCLUSIONS This study indicates that significant changes occur in the hepatic GSH homeostasis after intraperitoneal GSH administration. The activity of hepatic GGT, most likely through degradation of circulating GSH, followed by an increase in cysteine availability, seems to account, at least partially, for the reported effects.
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Affiliation(s)
- G Vendemiale
- Dept. of Internal Medicine, University of Bari, Italy
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Hirai M, Iwamura S, Varghese G, Speisky H, Israel Y. Reciprocal gamma-glutamyl transferase and cystathionase activity in guinea pig, rat and human liver. J Hepatol 1994; 21:683-4. [PMID: 7814816 DOI: 10.1016/s0168-8278(94)80119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Hinchman CA, Ballatori N. Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1994; 41:387-409. [PMID: 8145281 DOI: 10.1080/15287399409531852] [Citation(s) in RCA: 111] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
By catalyzing the reaction of electrophilic compounds with the sulfhydryl group of glutathione, the glutathione S-transferases play physiologically important roles in the detoxication of potential alkylating agents. The glutathione S-conjugates thus formed are transported out of cells for further metabolism by gamma-glutamyltransferase and dipeptidases, ectoproteins that catalyze the sequential removal of the glutamyl and glycyl moieties, respectively. These ectoproteins are not found in all cells, but are localized predominantly to the apical surface of epithelial tissues. The resulting cysteine S-conjugates can be reabsorbed by specific cell types, and acetylated on the amino group of the cysteinyl residue by intracellular N-acetyl-transferases, to form the corresponding mercapturic acids (N-acetylcysteine S-conjugates). Mercapturic acids are then released into the circulation and delivered to the kidney for excretion in urine, or they may undergo further metabolism. Mercapturic acid biosynthesis is generally considered to be an interorgan process, with the liver serving as the major site of glutathione conjugation, and the kidney as the primary site for conversion of glutathione conjugates to cysteine conjugates. Cysteine conjugates formed in the kidney appear to be transported back to the liver for acetylation. This interorgan model of mercapturic acid synthesis is based largely on the interorgan distribution of the enzymes involved in their formation, and in particular of the enzyme gamma-glutamyltransferase. Rats have relatively low hepatic and high renal activities of gamma-glutamyltransferase, the only protein known to initiate the breakdown of glutathione S-conjugates. The low gamma-glutamyltransferase activity in rat liver limits the hepatic degradation of glutathione S-conjugates, particularly after large doses of xenobiotic. In contrast, hepatic gamma-glutamyltransferase is significantly higher in species such as rabbit, guinea pig, and dog, and as a consequence, nearly all of the glutathione and glutathione S-conjugates released by liver cells of these species is degraded within the liver. Recent studies demonstrate that glutathione S-conjugates synthesized within hepatocytes are secreted preferentially across the canalicular membrane into bile, and are broken down within biliary spaces to form cysteine S-conjugates. The latter are then reabsorbed by the liver, N-acetylated to form mercapturic acids, and reexcreted into bile, completing an intrahepatic pathway for mercapturic acid biosynthesis. The contribution of this intrahepatic pathway to overall mercapturate formation is dependent on dose of the electrophile, route of exposure, and the physicochemical properties of the glutathione S-conjugate formed, as well as the tissue distribution and activity of gamma-glutamyltransferase.(ABSTRACT TRUNCATED AT 400 WORDS)
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Affiliation(s)
- C A Hinchman
- Department of Environmental Medicine, University of Rochester School of Medicine, NY 14642
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Irita K, Okabe H, Koga A, Kurosawa K, Tagawa K, Yamakawa M, Yoshitake J, Takahashi S. Carbon tetrachloride increases sinusoidal efflux of reduced and oxidized glutathione in rats. Biochem Pharmacol 1994; 47:447-52. [PMID: 8117311 DOI: 10.1016/0006-2952(94)90174-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
To elucidate the significance of the changes in plasma glutathione concentrations associated with carbon tetrachloride (CCl4)-induced liver damage, the changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in plasma as well as in the liver were investigated in rats. In the liver, the concentration of GSH decreased, and that of GSSG increased 24 hr after the intraperitoneal administration of CCl4. In the right atrial plasma, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased as did that in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic inferior vena cava from those of the suprahepatic inferior vena cava. The net efflux of GSH and GSSG started to increase as early as 3-6 hr after CCl4 administration, and reached a plateau 6 and 24 hr after CCl4 administration, respectively. On the other hand, an elongation of prothrombin time and leakage of alanine aminotransferase reached a maximum 24 and 48 hr after CCl4 administration, respectively. Vacuolization in the centri-lobular region and inflammatory infiltration started 3 and 6 hr after CCl4 administration, respectively, and progressed for 48 hr. These results suggest that CCl4 induced an increase in plasma concentrations of GSH as well as GSSG by increasing their efflux from the liver, and that the changes in plasma glutathione status might be a useful and sensitive marker for CCl4-induced liver damage.
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Affiliation(s)
- K Irita
- Department of Anesthesiology and Critical Care Medicine, Kyushu University School of Medicine, Fukuoka, Japan
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Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1993; 43:667-9. [PMID: 1362956 DOI: 10.1007/bf02284971] [Citation(s) in RCA: 155] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.
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Affiliation(s)
- A Witschi
- Department of Clinical Pharmacology, University of Bern, Switzerland
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Abstract
The biochemistry of alcohol liver disease as it relates to clinical medicine and experimental alcohol liver disease is presented. Clinical features are emphasized in the diagnosis of alcohol liver disease, particularly as it relates to staging the disease and predictors of prognosis. Currently, it is true that the biochemical diagnosis of alcohol liver disease is at best very limited in terms of the sensitivity tests and specificity of the test. It is particularly difficult to detect alcohol liver disease biochemically in the early stages when steatohepatitis is not severe. Consequently, 50% of the patients have already developed cirrhosis at the time they are diagnosed clinically. In this review indicators of malnutrition are emphasized because they have the strongest implications regarding survival during the acute hospitalization stage of the disease. They are also the best indicators of response to therapy during the recovery phase. With respect to experimental work on the pathogenesis of alcohol liver disease, it appears that necrosis is due to the inability to increase blood flow to compensate for increased oxygen utilization. The hypothesis that mitochondrial damage is the cause of liver cell damage is regarded as less important in the pathogenesis of necrosis. The shift in the redox state during alcohol metabolism accounts for the fatty change noted in the central lobular area of the liver in animals fed alcohol. Apparently, there is strong experimental evidence that highly reactive intermediates are important in the pathogenesis of liver damage due to the induction of the isozyme cytochrome P450 IIE1 by alcohol ingestion. This mechanism is enhanced by a diet high in polyunsaturated fatty acids.
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Affiliation(s)
- S W French
- Department of Pathology, Harbor-UCLA Medical Center, Torrance
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Lança AJ, Israel Y. Histochemical demonstration of sinusoidal gamma-glutamyltransferase activity by substrate protection fixation: comparative studies in rat and guinea pig liver. Hepatology 1991; 14:857-63. [PMID: 1718834 DOI: 10.1002/hep.1840140518] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Most histochemical methods for the detection of an enzymatic activity are preceded by tissue fixation with chemical agents that partially inactivate the enzymes. It is well known that substrates exert a marked protection against fixative-induced inactivation. The conventional histochemical methods for the demonstration of hepatic gamma-glutamyltransferase activity have not been successful in detecting the activity of the enzyme on the sinusoidal side of the hepatocytes despite mounting biochemical evidence for its presence on that pole of the hepatocyte. Under conventional fixation the enzymatic activity in hepatocytes is only seen on the bile canalicular side. This may be the result of a preferential protective effect of gamma-glutamyltransferase by its normal substrate, glutathione, present in the bile canaliculus at concentrations 500 times higher than in the sinusoidal lumen (8 mmol/L vs. 10 to 20 mumol/L). To test this hypothesis and to reduce the degree of fixative-induced inhibition of the enzyme activity, glutathione was either incorporated in the fixative solution or the livers were perfused with high concentrations of glutathione (10 mmol/L) before fixation. Our results histochemically demonstrate, in the normal adult rat liver, the existence of gamma-glutamyltransferase activity not only on the bile canalicular pole but also on the sinusoidal pole of the hepatocytes. Visualization of the enzyme activity on the sinusoidal pole is dependent on glutathione protection. Guinea pig livers, which present a 10-fold higher gamma-glutamyltransferase activity than rat livers (similar to that in human beings), showed marked sinusoidal gamma-glutamyltransferase activity even in the absence of glutathione protection. Glutathione protection further increased this sinusoidal activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- A J Lança
- Department of Pharmacology, University of Toronto, Ontario, Canada
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Speisky H, Israel Y. Gamma-glutamyl transferase ectoactivity in the intact rat liver: effect of chronic alcohol consumption. Alcohol 1990; 7:339-47. [PMID: 1975183 DOI: 10.1016/0741-8329(90)90093-r] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The localization of gamma-glutamyl transferase (GGT) in the intact rat liver was studied by a new approach in which the chromogenic gamma-glutamyl donor substrate of GGT gamma-glutamyl-p-nitroanilide is perfused through the portal vein to yield p-nitroaniline, which is monitored spectrophotometrically. GGT activity was markedly increased by the gamma-glutamyl acceptors glycyl-glycine, cystine and methionine, following Michaelis-Menten kinetics. Infusion of glutathione (GSH), the natural substrate of GGT, was shown to markedly reduce or to abolish the formation of p-nitroaniline without entering the liver cells, indicating the existence of a GGT ectoactivity accessible to the sinusoidal circulation. This ectoenzyme was shown to remove significant amounts of GSH from the circulation, amounting, in the naive rat, to 20-25% of the net rate at which GSH is contributed by the liver into the circulation. Chronic alcohol consumption is known to increase hepatic GGT activity, although the biological significance of such an effect remains unknown. Present studies show that chronic administration of alcohol to rats leads to a significant (40-75%) increase in hepatic GGT ectoactivity. GGT ectoactivity significantly correlates with total liver GGT, both in control and alcohol-treated animals (r = .76 and r = .90, respectively). Livers of alcohol-fed rats showed an increased (80-110%) capacity to remove circulating GSH which strongly correlated with total liver GGT (r = .96; p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- H Speisky
- Department of Pharmacology, University of Toronto, Ontario, Canada
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