Amitava Dasgupta received his Ph. D in chemistry from Stanford University and completed his fellowship training in Clinical Chemistry from the Department of Laboratory Medicine at the University of Washington School of Medicine at Seattle. He is board certified in both Toxicology and Clinical Chemistry by the American Board of Clinical Chemistry. Currently, he is a tenured Full Professor of Pathology and Laboratory Medicine at the University of Kansas Medical Center and Director of Clinical Laboratories at the University of Kansas Hospital. Prior to this appointment he was a tenured Professor of Pathology and Laboratory Medicine at the University of Texas McGovern medical School from February 1998 to April 2022. He has 252 papers to his credit. He is in the editorial board of four journals including Therapeutic Drug Monitoring, Clinica Chimica Acta, Archives of Pathology and Laboratory Medicine, and Journal of Clinical Laboratory Analysis.
Alcohol and Its Biomarkers: Clinical Aspects and Laboratory Determination is a concise guide to all currently known alcohol biomarkers, their clinical application, and the laboratory methods used to detect them. Pathologists can use this resource to understand the limitations and cost factors associated with each method for determining certain alcohol biomarkers. In addition, interferences in these determinations are discussed, so that clinicians can understand the causes of falsely elevated biomarkers and pathologists and laboratory scientists can potentially eliminate them. The book focuses on the analytical methods used to detect alcohol in blood and urine, the limitations of alcohol determination using enzymatic methods, and the differences between clinical and forensic alcohol measurement. Chapters also cover cutting-edge alcohol biomarkers for potential use. - Focuses on the analytical methods used for detecting alcohol in blood and urine along with the pitfalls and limitations of alcohol determination using enzymatic methods- Explains the difference between clinical and forensic alcohol measurement- Includes a brief overview of the benefits of consuming alcohol in moderation and the hazards of heavy drinking
Front Cover 1
Alcohol and Its Biomarkers 4
Copyright Page 5
Contents 6
Preface 12
1 Alcohol 14
1.1 Introduction 14
1.2 Alcohol Consumption: Historical Perspective 15
1.3 Alcohol Content of Various Alcoholic Beverages 16
1.4 Guidelines for Alcohol Consumption 17
1.5 Benefits of Drinking in Moderation 19
1.5.1 Moderate Alcohol Consumption and Reduced Risk of Cardiovascular Disease 20
1.5.2 Is Red Wine More Effective than other Alcoholic Beverages for Protecting the Heart? 23
1.5.3 Moderate Consumption of Alcohol and Reduced Risk of Stroke 23
1.5.4 Moderate Consumption of Alcohol and Reduced Risk of Developing Metabolic Syndrome and Type 2 Diabetes 24
1.5.5 Moderate Alcohol Consumption and Reduced Risk of Dementia/Alzheimer’s Disease 26
1.5.6 Association between Moderate Alcohol Consumption and Reduced Cancer Risk 26
1.5.7 Can Moderate Alcohol Consumption Prolong Life? 27
1.5.8 Moderate Alcohol Consumption and Reduced Risk of Arthritis 28
1.5.9 Moderate Alcohol Consumption and Reduced Chance of Getting the Common Cold 28
1.6 Adverse Heath Effects Related to Alcohol Dependence 29
1.6.1 Liver Diseases and Cirrhosis of the Liver Associated with Alcohol Abuse 29
1.6.2 Alcohol Abuse and Neurological Damage 31
1.6.3 Alcohol Abuse and Increased Risk of Cardiovascular Disease and Stroke 34
1.6.4 Alcohol Abuse and Damage to the Immune System 34
1.6.5 Alcohol Abuse and Damage to the Endocrine System and Bone 35
1.6.6 Alcohol Abuse Increases the Risk of Certain Cancers 35
1.6.7 Fetal Alcohol Syndrome 36
1.6.8 Alcohol Abuse and Reduced Life Span 37
1.6.9 Alcohol Abuse and Violent Behavior/Homicide 38
1.6.10 Alcohol Poisoning 39
1.7 Blood Alcohol Level 40
1.7.1 Alcohol Odor on Breath and Endogenous Alcohol Production 42
1.8 Conclusions 43
References 43
2 Genetic Aspects of Alcohol Metabolism and Drinking Behavior 50
2.1 Introduction 50
2.2 Alcohol Absorption: Effect of Food 50
2.3 First-Pass Metabolism of Alcohol 52
2.4 Alcohol Metabolism 53
2.4.1 Non-Oxidative Pathways of Alcohol Metabolism 55
2.4.2 Factors Affecting Alcohol Metabolism 56
2.5 Genes Encoding Alcohol Dehydrogenase 58
2.5.1 Polymorphism of Alcohol Dehydrogenase Genes 59
2.6 Genes Encoding Aldehyde Dehydrogenase 61
2.6.1 Polymorphisms of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Genes that Protect Against the Development of Alcoh... 64
2.6.2 Polymorphism of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Genes that may Increase the Risk of Developing Alcoh... 69
2.7 Polymorphism of the CYP2E1 Gene 72
2.8 Conclusions 72
References 73
3 Measurement of Alcohol Levels in Body Fluids and Transdermal Alcohol Sensors 78
3.1 Introduction 78
3.2 Breath Alcohol Determination 81
3.2.1 Chemical Principle of Breath Alcohol Analyzers 82
3.2.2 Effect of Breathing Pattern on Breath Alcohol Test Results 84
3.2.3 Interference in Various Breath Alcohol Analyzers 84
3.3 Blood Alcohol Determination 87
3.3.1 Enzymatic Alcohol Assays and Limitations 88
3.3.2 Gas Chromatography in Blood Alcohol Determination 91
3.3.3 Stability of Alcohol in Blood During Storage 92
3.3.4 Correlation between Blood and Breath Alcohol 93
3.4 Endogenous Production of Alcohol 94
3.5 Urine Alcohol Determination 95
3.6 Saliva Alcohol Determination 97
3.7 Transdermal Alcohol Sensors 98
3.8 Conclusions 100
References 100
4 Alcohol Biomarkers 104
4.1 Introduction 104
4.2 State Versus Trait Alcohol Biomarkers 105
4.3 Liver Enzymes as Alcohol Biomarkers 107
4.4 Mean Corpuscular Volume as Alcohol Biomarker 110
4.5 Carbohydrate-Deficient Transferrin as Alcohol Biomarker 111
4.5.1 Combined CDT–GGT as Alcohol Biomarker 113
4.6 ß-Hexosaminidase as Alcohol Biomarker 114
4.7 Ethyl Glucuronide and Ethyl Sulfate as Alcohol Biomarkers 115
4.8 Fatty Acid Ethyl Ester as Alcohol Biomarker 117
4.9 Phosphatidylethanol as Alcohol Biomarker 119
4.10 Total Plasma Sialic Acid as Alcohol Biomarker 121
4.11 Sialic Acid Index of Apolipoprotein J 122
4.12 5-HTOL/5-HIAA as Alcohol Biomarker 122
4.13 Other Alcohol Biomarkers 123
4.14 Clinical Application of Alcohol Biomarkers 124
4.14.1 Diagnosis Using DSM-IV and DSM-5 124
4.14.2 Self-Assessment of Alcohol Use 124
4.14.3 Alcohol Biomarkers and AUDIT 125
4.14.4 Application of Alcohol Biomarkers 126
4.14.5 Combining Alcohol Biomarkers 127
4.15 Conclusions 129
References 129
5 Liver Enzymes as Alcohol Biomarkers 134
5.1 Introduction 134
5.2 Factors Affecting Liver Function Tests 135
5.3 Effect of Moderate Alcohol Consumption on Liver Enzymes 138
5.4 GGT as Alcohol Biomarker 139
5.4.1 Elevated GGT in Various Diseases and as a Risk Factor for Mortality and Certain Illnesses 143
5.4.2 GGT Fraction as Alcohol Biomarker 145
5.5 Laboratory Determinations of Liver Enzymes 146
5.6 Conclusions 147
References 147
6 Mean Corpuscular Volume and Carbohydrate-Deficient Transferrin as Alcohol Biomarkers 152
6.1 Introduction 152
6.2 Mean Corpuscular Volume as Alcohol Biomarker 152
6.2.1 Mechanism of Increased MCV in Alcoholics 154
6.2.2 Other Causes of Macrocytosis 154
6.3 Carbohydrate-Deficient Transferrin 155
6.3.1 Mechanism of Formation of CDT 157
6.3.2 Cutoff Values, Sensitivity, and Specificity of CDT 157
6.3.3 CDT and GGT as Combined Alcohol Biomarker 160
6.3.4 Application of CDT 161
6.3.5 Limitations of CDT as Alcohol Biomarker 164
6.4 Laboratory Determination of CDT 167
6.5 Conclusions 171
References 171
7 ß-Hexosaminidase, Acetaldehyde–Protein Adducts, and Dolichol as Alcohol Biomarkers 176
7.1 Introduction 176
7.2 ß-Hexosaminidase Isoforms 176
7.3 ß-Hexosaminidase as Alcohol Biomarker 177
7.3.1 Pathophysiological Conditions that Cause Elevated Levels of ß-Hexosaminidase 181
7.4 Laboratory Methods for Measuring ß-Hexosaminidase 184
7.5 Acetaldehyde–Protein Adducts as Alcohol Biomarkers 185
7.5.1 Acetaldehyde–Hemoglobin Adducts 186
7.5.2 Acetaldehyde–Erythrocyte Protein Adducts 187
7.5.3 IgA Antibody Against Acetaldehyde-Modified Bovine Serum Albumin 188
7.6 Dolichol as Alcohol Biomarker 188
7.7 Conclusions 190
References 190
8 Direct Alcohol Biomarkers Ethyl Glucuronide, Ethyl Sulfate, Fatty Acid Ethyl Esters, and Phosphatidylethanol 194
8.1 Introduction 194
8.2 Ethyl Glucuronide and Ethyl Sulfate 195
8.3 Ethyl Glucuronide and Ethyl Sulfate as Alcohol Biomarkers 199
8.3.1 Ethyl Glucuronide and Ethyl Sulfate Observed Due to Incidental Exposure to Alcohol 201
8.3.2 Ethyl Glucuronide and Ethyl Sulfate Cutoff Concentrations in Urine 204
8.3.3 Ethyl Glucuronide and Ethyl Sulfate Cutoff Concentrations in Hair, Meconium, and other Matrices 205
8.3.4 False-Positive/False-Negative Results with Ethyl Glucuronide 207
8.3.5 Application of Ethyl Glucuronide and Ethyl Sulfate as Alcohol Biomarkers 209
8.3.6 Laboratory Methods for Determination of Ethyl Glucuronide and Ethyl Sulfate 212
8.4 Fatty Acid Ethyl Esters as Alcohol Biomarkers 214
8.4.1 Fatty Acid Ethyl Esters in Hair 215
8.4.2 Fatty Acid Ethyl Esters in Meconium 217
8.4.3 Laboratory Analysis of Fatty Acid Ethyl Esters 219
8.5 Phosphatidylethanol as Alcohol Biomarker 220
8.5.1 Cutoff Concentration of Phosphatidylethanol 223
8.5.2 Laboratory Analysis of Phosphatidylethanol 224
8.6 Sensitivity and Specificity of Direct Alcohol Biomarkers 226
8.7 Conclusions 228
References 228
9 Less Commonly Used Alcohol Biomarkers and Proteomics in Alcohol Biomarker Discovery 234
9.1 Introduction 234
9.2 Total Sialic Acid in Serum as Alcohol Biomarker 234
9.2.1 Other Causes of Elevated Plasma Sialic Acid Concentrations 237
9.2.2 Laboratory Determination of Total Sialic Acid 238
9.3 Sialic Acid Index of Apolipoprotein J as Alcohol Biomarker 240
9.3.1 Laboratory Methods for the Determination of the Sialic Acid Index of Plasma Apolipoprotein J 242
9.4 5-Hydroxytryptophol as Alcohol Biomarker 243
9.4.1 Laboratory Methods for Determining 5-HTOL and 5-HIAA 248
9.5 Other Alcohol Biomarkers 249
9.6 Proteomics in Alcohol Biomarker Discovery 250
9.6.1 Specific Proteins Identified as Alcohol Biomarkers Using the Proteomics Approach 251
9.7 Conclusions 254
References 254
10 Genetic Markers of Alcohol Use Disorder 258
10.1 Introduction 258
10.2 Heredity, Environment, and Alcohol Use Disorder 259
10.2.1 Effect of Nongenetic Factors on the Development of Alcohol Use Disorder 260
10.3 Genes and Alcohol Use Disorder: An Overview 261
10.4 Polymorphisms in Genes Encoding Alcohol Dehydrogenase and Aldehyde Dehydrogenase 263
10.4.1 Polymorphisms that Protect from Alcohol Use Disorder 264
10.4.2 Polymorphisms that may Increase the Risk of Alcohol Use Disorder 266
10.5 Neurobiological Basis of Alcohol Use Disorder 266
10.6 Polymorphisms of Genes in Dopamine Pathway and Alcohol Use Disorder 267
10.6.1 Dopamine Receptors 268
10.6.2 Dopamine Transporters and Dopamine-Metabolizing Enzymes 271
10.6.3 Monoamine Oxidase 272
10.6.4 Catechol-O-Methyltransferase 272
10.7 Polymorphisms of Genes in the Serotonin Pathway and Alcohol Use Disorder 273
10.8 Polymorphisms of Genes in the Gaba Pathway and Alcohol Use Disorder 277
10.9 Polymorphisms of Genes Encoding Cholinergic Receptors and Alcohol Use Disorder 280
10.10 Polymorphisms of Genes in the Glutamate Pathway and Alcohol Use Disorder 282
10.11 Polymorphisms of Genes Encoding Opioid Receptors and Alcohol Use Disorder 285
10.12 Polymorphisms of Genes Encoding Cannabinoid Receptors and Alcohol Use Disorder 287
10.13 Adenylyl Cyclase and Alcohol Use Disorder 288
10.14 Neuropeptide Y and Alcohol Use Disorder 290
10.15 Possible Association of Polymorphisms of other Genes With Alcohol Use Disorder 291
10.16 Epigenetics and Alcohol Use Disorder 291
10.17 Conclusions 294
References 294
Index 302
Genetic Aspects of Alcohol Metabolism and Drinking Behavior
This chapter discusses the various pathways of alcohol metabolism, including alternative pathways in alcoholics that may cause the generation of free radicals and oxidative stress. Gender differences in alcohol metabolism and the effect of food on alcohol absorption are also addressed.
Keywords
Alcohol metabolism; alcohol dehydrogenase; aldehyde dehydrogenase; polymorphism
Contents
2.2 Alcohol Absorption: Effect of Food 37
2.3 First-Pass Metabolism of Alcohol 39
2.4.1 Non-Oxidative Pathways of Alcohol Metabolism 42
2.4.2 Factors Affecting Alcohol Metabolism 43
2.5 Genes Encoding Alcohol Dehydrogenase 45
2.5.1 Polymorphism of Alcohol Dehydrogenase Genes 46
2.6 Genes Encoding Aldehyde Dehydrogenase 48
2.7 Polymorphism of the CYP2E1 Gene 59
References 60
2.1 Introduction
Ethanol, commonly referred to as “alcohol,” is a small water-soluble polar molecule with a molecular weight of 46. The ethanol molecule contains a hydroxyl (–OH) functional group. Alcohol (ethanol) is a nutrient with a caloric value of approximately 7 kcal/g, whereas protein has a caloric value of 4 kcal/g and fat produces 9 kcal/g. After ingestion, alcohol is readily absorbed, but a small amount also undergoes first-pass metabolism. Absorption of alcohol from the gastrointestinal tract depends on how fast the person is drinking as well as whether or not alcohol is consumed with food. After absorption, alcohol is distributed in various tissues and also undergoes extensive metabolism and finally elimination. Although the majority of alcohol is metabolized via the oxidative pathway mainly involving two enzymes—alcohol dehydrogenase and aldehyde dehydrogenase—a small amount is also oxidized by the liver cytochrome P450 enzyme system, most commonly CYP2E1, especially in the presence of a high blood alcohol level. Other enzymes, such as catalase, may also be capable of metabolizing alcohol, but they represent a minor pathway. Polymorphisms of genes coding both alcohol dehydrogenase and aldehyde dehydrogenase enzymes affect blood alcohol level, and some polymorphisms may protect an individual from alcohol abuse. Minor non-oxidative metabolic pathways for alcohol involve conjugation with glucuronic acid yielding ethyl glucuronide and conjugation with sulfate to produce ethyl sulfate.
2.2 Alcohol Absorption: Effect of Food
Alcohol is absorbed from both the stomach and small intestine. A small amount of alcohol that is not absorbed is found in the breath and is the basis of breath analysis of drivers suspected of driving while intoxicated. In general, it is assumed that approximately 1–5% of alcohol is excreted by the lungs, and 1–3% is excreted via other routes such as urine (0.5–2.0%) and sweat (up to 0.5%). A very small amount of alcohol is also metabolized by non-oxidative pathways, and products of such reactions are often used as alcohol biomarkers, such as ethyl glucuronide and ethyl sulfate. The overall elimination process of alcohol can be described by a capacity-limited model similar to the Michaelis–Menten model of enzyme kinetics [1]. When alcohol is consumed, approximately 20% is absorbed by the stomach and the rest is absorbed by the small intestine by passive diffusion. A peak concentration is usually achieved 30–60 min after consumption. Food substantially slows the absorption of alcohol, and sipping of alcohol instead of drinking also slows the absorption of alcohol from the gastrointestinal tract. The presence of food in the stomach before alcohol consumption delays gastric emptying and reduces the rate of delivery of alcohol in the duodenum, thus reducing the alcohol absorption rate.
The effect of food on absorption and metabolism of alcohol has been widely studied and reported in the medical literature. In one study, 10 healthy men took in, via drinking, a moderate dosage of alcohol (0.80 g of alcohol per kilogram of body weight) in the morning after an overnight fast or immediately after breakfast (two cheese sandwiches, one boiled egg, orange juice, and fruit yogurt). Subjects who consumed alcohol on an empty stomach felt more intoxicated than those who consumed the same amount of alcohol after eating breakfast. The blood alcohol analysis revealed that the average peak blood alcohol in subjects who consumed alcohol on an empty stomach was 104 mg/dL. In contrast, the average peak blood alcohol in subjects who consumed alcohol after eating breakfast was 67 mg/dL. The time required to metabolize the total amount of alcohol was on average 2 hr shorter in subjects who consumed alcohol after eating breakfast compared to subjects who consumed alcohol on an empty stomach. The authors concluded that food in the stomach before alcohol consumption not only reduces the peak blood alcohol concentration but also increases elimination of alcohol from the body [2]. The effect of the nature of the food, such as high fat versus high protein or high carbohydrate, on the magnitude of the reduction of absorption of alcohol has also been studied. Jones et al. reported that the average peak blood alcohol level was 30.8 mg/dL in volunteers when alcohol was consumed on an empty stomach, but levels were respectively 16.6, 17.77, and 13.3 mg/dL when alcohol was consumed after eating a fatty meal, a meal rich in carbohydrates, or a meal rich in protein. The peak blood concentration was reached between 30 and 60 min after alcohol was consumed on an empty stomach or after eating a meal rich in protein. However, peak alcohol level was reached between 30 and 90 min when alcohol was consumed after eating a meal rich in fat or rich in carbohydrates. As expected, intravenous infusion of alcohol resulted in a higher average blood alcohol level of 54.3 mg/mL, and peak blood alcohol was observed within 30 min. The authors concluded that regardless of the composition of the meal, food in the stomach decreases the systemic availability of alcohol, probably due to slower gastric emptying time. Moreover, with food in the stomach, a portion of alcohol may be trapped by the constituents of the meal [3].
2.3 First-Pass Metabolism of Alcohol
After alcohol is ingested, a small portion of alcohol enters the hepatic portal system and undergoes first-pass metabolism (FPM) by the liver, but gut alcohol dehydrogenase enzymes also play an important role in FPM of alcohol. Lim et al. commented that FPM of alcohol is predominantly gastric in nature [4]. In relation to alcohol, many factors affect FPM of alcohol, including gastrointestinal motility, nutritional status, liver function, gender, and age, as well as the genetic makeup of the person. After drinking the same amount of alcohol, men have a lower peak blood alcohol level compared to women with the same body weight. This gender difference in the blood alcohol level is partly related to the different body water content in men and women: women have a lower amount of body water (52% body water content is the average in women) compared to men (61% average). Therefore, less body water is available to dissolve the same amount of alcohol, which is water soluble, in women compared to men. However, gender difference in the rate of metabolism of alcohol by the alcohol dehydrogenase enzyme present in gastric mucosa is also responsible for higher blood alcohol in women compared to men with same body weight after consumption of the same amount of alcohol. Ammon et al. reported that total FPM on average accounted for 9.1% of alcohol metabolism in men and 8.4% in women. Dose-corrected values for the area under the blood alcohol concentration–time curves (AUC) over time were on average 28% higher in women than in men [5]. Marshall et al., who studied 9 normal women and 10 normal men, observed that, after oral ethanol administration (0.5 g/kg body weight), women showed higher peak blood alcohol levels than did men (mean: 88 mg/dL in women and 75 mg/dL in men). The mean apparent volume of distribution of alcohol was 0.59 L/kg in females and 0.73 L/kg in men. Both apparent volume of distribution of alcohol and AUC were significantly correlated with total body water (measured by 3H water dilution), suggesting that gender difference in ethanol pharmacokinetics may be related to gender difference relating to body water content [6].
First-pass metabolism of alcohol by gastric alcohol dehydrogenase (ADH) is slightly higher in men than in women, and this may be related to higher ADH activity in men than in women, especially women younger than age 50 years. Commonly used drugs, such as acetaminophen, aspirin, and H2 blockers (ranitidine, cimetidine, etc.), may decrease the activity of gastric ADH, thus reducing FPM of alcohol. As a result, elevated...
| Erscheint lt. Verlag | 18.2.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Naturwissenschaften ► Biologie ► Biochemie | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Humanbiologie | |
| ISBN-10 | 0-12-800409-6 / 0128004096 |
| ISBN-13 | 978-0-12-800409-8 / 9780128004098 |
| Haben Sie eine Frage zum Produkt? |
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