First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. In the early days of the serial, the subjects of vitamins and hormones were quite distinct. The Editorial Board now reflects expertise in the field of hormone action, vitamin action, X-ray crystal structure, physiology, and enzyme mechanisms. Under the capable and qualified editorial leadership of Dr. Gerald Litwack, Vitamins and Hormones continues to publish cutting-edge reviews of interest to endocrinologists, biochemists, nutritionists, pharmacologists, cell biologists, and molecular biologists. Others interested in the structure and function of biologically active molecules like hormones and vitamins will, as always, turn to this series for comprehensive reviews by leading contributors to this and related disciplines.
Front Cover 1
Vitamin E 4
Copyright Page 5
Dedication Page 6
Contents 8
Contributors 18
Preface 22
Chapter 1: Vitamin E 24
I. Introduction 25
II. Vitamin E Structures and Function 26
III. Absorption, Transport, and Distribution to Tissues 27
A. Vitamin E Absorption 27
B. Requirement for Dietary Fat for Absorption 27
C. Requirement for Chylomicron Synthesis 28
D. Role of Exchange Proteins 28
E. Secretion of alpha-Tocopherol by the Liver 29
IV. The alpha-Tocopherol Transfer Protein 29
A. Structure and Localization 29
B. CRAL-TRIO Family 30
V. Regulation of Vitamin E Metabolism and Excretion 31
A. What Is CEHC? 31
B. Metabolism of Vitamin E 32
C. Conjugation of CEHCs 35
D. Biliary Excretion of alpha-Tocopherol 36
E. Implications of Altered Xenobiotic Metabolism 36
VI. Implications for Humans Supplementing with Vitamin E 37
VII. Conclusion 39
Acknowledgments 39
References 39
Chapter 2: Structure and Function of alpha-Tocopherol Transfer Protein: Implications for Vitamin E Metabolism and AVED 46
I. Introduction 47
II. Structure of alpha-TTP 52
A. Crystallization 52
B. Overall Fold 52
C. Ligand Binding by alpha-TTP 53
D. An Open Conformation of alpha-TTP 55
III. Mutations Associated with AVED 57
A. Structural Considerations 57
B. Biochemical Characterization of AVED-Associated Mutants 61
IV. Summary 62
References 63
Chapter 3: The alpha-Tocopherol Transfer Protein 68
I. Introduction 69
II. Identification of TTP 70
III. TTP and Vitamin E Status: Ataxia with Vitamin E Deficiency 71
IV. TTP and Vitamin E Status: TTP-/- Mice 74
V. Biochemical Activities of TTP 74
A. Specific, High-Affinity Binding of RRR-alpha-TOH 75
B. Facilitation of Ligand Transfer Between Lipid Vesicles 76
VI. Physiological Activities of TTP 76
VII. Three-Dimensional Structure of TTP 79
VIII. Selective Retention of RRR-alpha-TOH and the Evolutionary Origins of TTP 81
IX. Epilogue 83
References 83
Chapter 4: Molecular Associations of Vitamin E 90
I. Introduction 91
II. Physical Properties of Vitamin E 93
III. Interaction of Vitamin E with Lipids in Monolayers 93
IV. Interaction of Vitamin E with Phospholipid Bilayer Membranes 96
V. Distribution and Orientation of Vitamin E in Phospholipid Membranes 97
VI. Motion of Vitamin E in Lipid Assemblies 99
VII. Effect of Vitamin E on Phospholipid Phase Behavior 100
VIII. Effect of Vitamin E on the Structure of Phospholipid Model Membranes 102
IX. Phase Separation of Vitamin E in Phospholipid Mixtures 108
X. Effect of Vitamin E on Membrane Permeability 111
XI. Effect of Vitamin E on Membrane Stability 112
XII. Domains Enriched in Vitamin E in Membranes 114
XIII. Effect of Vitamin E on Membrane Protein Function 115
XIV. Conclusions 116
References 116
Chapter 5: Studies in Vitamin E: Biochemistry and Molecular Biology of Tocopherol Quinones 122
I. Introduction 123
II. Redox Cycling and Arylating Properties of Tocopherol Quinones 126
A. Redox Cycling 126
B. Arylation 127
III. Identification and Analysis of Tocopherols, Quinones, and Adducts 131
A. Tocopherols and Their Quinones 131
B. Thiol Nucleophile Adducts 132
IV. Arylating Tocopherol Quinones and the Unfolded Protein Response 134
V. Tocopherol Quinones and.Mutagenesis 135
VI. Specificity of Phenolic Antioxidant Precursors in Tocopherol Biology 136
A. The alpha-T Story 136
B. The Multifaceted Effects of gamma-T and gamma-CEHC 138
C. Similarities and Differences Between Tocopherols and Tocotrienols 141
VII. Natural Abundance of Tocopherols and Its Effects on Biology 141
A. Plant Sources and the Origins of the Mediterranean and Modern Diets 141
B. The Breast Milk/Infant Formula Conundrum 143
C. Generation of Arylating Tocopherol Quinones in Vegetable Cooking Oils 144
Acknowledgments 145
References 145
Chapter 6: Vitamin E and NF-kappaB Activation: A Review 158
I. Introduction 159
II. Nuclear Factor-kappaB 160
III. In Vitro Studies 161
A. Immune System 162
B. Cardiovascular 163
C. Neural 163
D. Liver 164
E. Epithelial Cells 164
F. Fibroblasts 164
G. Other 165
IV. In Vivo Studies 165
V. Mechanisms by Which Vitamin E May Inhibit NF-kappa B Activation 166
VI. Is the Inhibition of NF-kappaB Activation Necessary for Some of the Activities of Vitamin E? 168
VII. Summary 168
References 168
Chapter 7: Synthesis of Vitamin E 178
I. Introduction 179
II. Synthesis of (All-rac)-alpha-Tocopherol 179
A. Building Blocks for the Aryl Containing Chroman Moiety 181
B. Side Chain Building Blocks 181
C. Synthesis of (all-rac)-alpha-Tocopherol 184
III. Preparation of Optically Active Tocopherols 188
A. Synthesis of Chiral Chroman Compounds 190
B. Synthesis of Chiral Side Chain Components 196
C. Synthesis of (R,R,R)-Tocopherols 200
D. Synthesis of Stereoisomers and Homologues Other Than (R,R,R)-alpha-Tocopherol 207
IV. Synthesis of Tocotrienols 211
References 217
Chapter 8: Tocotrienols: The Emerging Face of Natural Vitamin E 226
I. Historical Developments and the Vitamin E Family 227
II. Biosynthesis of Tocopherols and Tocotrienols 229
III. Changing Trends in Vitamin E Research 231
IV. Unique Biological Functions of Tocotrienols 233
V. Natural Sources of Tocotrienols 235
VI. Bioavailability of Oral Tocotrienols 236
VII. Biological Functions 240
A. Neuroprotection 252
B. Anticancer 257
C. Cholesterol Lowering 267
VIII. Conclusion 270
Acknowledgments 271
References 271
Chapter 9: Vitamin E Biotransformation in Humans 286
I. Introduction 287
II. The Fate of Vitamin E from Ingestion to Excretion 287
III. Biotransformation and Metabolism of Vitamin E as Bioactivation Processes 289
Acknowledgments 300
References 300
Chapter 10: alpha-Tocopherol Stereoisomers 304
I. Introduction 306
II. Sources of Tocopherol, Nomenclature, and Bioactivity 307
A. Presence in Food/Feed Ingredients 307
B. Nomenclature 307
C. Bioactivity and Bioavailability 308
III. Analytical Methods for Separation of alpha-Tocopherol Stereoisomers 311
A. GC and LC Methods 312
B. Deuterium-Labeling and Mass Spectrometry 314
IV. Bioavailability and Secretion into Milk 316
A. Rats 316
B. Pigs 319
C. Humans 322
D. Mink 324
E. Poultry 324
F. Ruminants 325
V. alpha-Tocopherol-Binding Protein (alpha-TTP) 326
VI. Conclusions 328
References 328
Chapter 11: Addition Products of alpha-Tocopherol with Lipid-Derived Free Radicals 332
I. Introduction 333
II. Addition Products of alpha-Tocopherol with Methyl Linoleate-Derived Free Radicals 334
III. Addition Products of alpha-Tocopherol with PC-Peroxyl Radicals in Liposomes 337
IV. Addition Products of alpha-Tocopherol with CE-Peroxyl Radicals 340
V. Detection of the Addition Products of alpha-Tocopherol with Lipid-Peroxyl Radicals in Biological Samples 341
References 347
Chapter 12: Vitamin E and Apoptosis 352
I. Introduction 353
II. Vitamin E and Vitamin E Derivatives 354
A. Natural Isoforms 354
B. Synthetic Dervivatives 356
III. Vitamin E Antioxidant Potency 357
IV. Vitamin E as an Anticancer Agent 359
A. Natural Forms 359
B. Synthetic Derivatives 361
V. Apoptosis 362
VI. Vitamin E Suppression of Apoptosis 364
VII. Vitamin E-Induced Apoptosis 365
A. Natural Forms 365
B. Synthetic Derivatives 369
VIII. Conclusion 371
References 371
Chapter 13: Vitamin E During Pre- and Postnatal Periods 380
I. Introduction 381
II. Prenatal Transfer of Vitamin E 382
A. Biochemical Aspects of the Transfer 382
B. Maternal Vitamin E Levels Increase During Pregnancy 384
C. Vitamin E Reserves of Fetuses and Newborns 385
III. Postnatal Transfer of Vitamin E 387
A. Mammary Gland Uptake 387
B. Milk Vitamin E and the Effect of Suckling on Vitamin E Status of Newborns 388
IV. Vitamin E in Critical Situations 389
A. Preterm Infants: More at Risk for a Vitamin E Deficiency 389
B. Vitamin E and Preeclampsia 390
References 391
Chapter 14: alpha-Tocopherol: A Multifaceted Molecule in Plants 398
I. Introduction 399
II. Occurrence and Antioxidant Function of alpha-Tocopherol in Plants 400
III. Photoprotective Function of alpha-Tocopherol in Plants 403
IV. alpha-Tocopherol and the Stability of Photosynthetic Membranes 406
V. Role of alpha-Tocopherol in Cellular Signaling 406
VI. Have the Functions of Tocopherols Been Evolutionary Conserved? 408
VII. Future Perspectives 410
References 410
Chapter 15: Vitamin E and Mast Cells 416
I. Introduction 417
A. Mast Cells 417
B. Vitamin E 418
II. Cellular Effects of Vitamin E in Mast Cells 420
A. Inhibition of Proliferation and Survival of Mast Cells by Vitamin E 420
B. Possible Molecular Targets for Vitamin E in Mast Cells 422
C. Mast Cell Degranulation and Vitamin E 426
III. Preventive Effects of Vitamin E on Diseases with Mast Cell Involvement 429
A. Vitamin E, Mast Cells, and Asthma 429
B. Vitamin E, Mast Cells, and Skin Diseases 430
C. Vitamin E, Mast Cells, and Atherosclerosis 431
IV. Summary 432
References 433
Chapter 16: Tocotrienols in Cardioprotection 442
I. Introduction 443
II. A Brief History of Vitamin 443
III. Vitamin E, Now and Then 444
IV. Tocotrienols versus Tocopherols 446
V. Sources of Tocotrienols 449
VI. Tocotrienols in Free Radical Scavenging and Antioxidant Activity 449
VII. Tocotrienols and Cardioprotection 450
VIII. Atherosclerosis 450
IX. Tocotrienols in Ischemic Heart Disease 452
X. Summary and Conclusion 453
Acknowledgments 453
References 453
Chapter 17: Vitamin E and Cancer 458
I. Basic Information About Vitamin E 459
A. How Many Vitamin Es Are There? 459
B. Why It Is so Important That the Form of Vitamin E Be Identified Properly? 461
C. Why Is RRR-alpha-Tocopherol the Most Bioavailable Form of Vitamin E? 462
D. Challenges for In Vivo Testing of Vitamin E Forms Other Than RRR-alpha-Tocopherol 463
II. Intervention Trials 464
A. What Have We Learned About Vitamin E and Cancer from Human Intervention Trials? 464
B. Conclusions 466
III. Preclinical Studies 466
A. Lack of Evidence for Anticancer Effects by RRR-alpha-Tocopherol or All-rac-alphaTocopherol 466
B. Evidence for Anticancer Effects of gamma-Tocopherol 467
C. Evidence for Anticancer Effects of Vitamin E Metabolites 467
D. Tocotrienols as Potential Anticancer Agents 468
E. Vitamin E Analogues as Potential Anticancer Agents 468
IV. Anticancer Mechanisms of Action of Vitamin E-Based Compounds 469
V. What About Vitamin E Supplementation and Cancer Survivorship? 476
VI. Conclusions 476
Acknowledgments 477
References 477
Chapter 18: Vitamin E Analogues and Immune Response in Cancer Treatment 486
I. Introduction 487
II. Vitamin E Analogues as Anticancer Agents 489
A. Vitamin E Analogues: Their Structure and Biological Activity 489
B. Initiation of Apoptotic Pathway by Mitochondria Destabilization 491
C. Deregulation of Signaling Pathways by Vitamin E Analogues 493
III. Vitamin E Analogues as Adjuvants in Cancer Chemotherapy 496
IV. Immunological Inducers of Apoptosis: Mechanisms and Clinical Application in Cancer 496
A. Death Receptor Signaling Pathway 496
B. CD95 Activation 498
C. Trail: A Promising Cancer Therapeutic 498
D. Factors Influencing Trail Sensitivity 499
E. Effect of Vitamin E Analogues on the Regulation of Death Receptors: Relevance for Cancer Therapy 500
V. Targeting Immune Surveillance 504
A. Immune Surveillance Against Tumor Development 504
B. Vitamin E Analogues as Adjuvants in Tumor Vaccination 505
VI. Conclusions 506
References 506
Chapter 19: The Roles of alpha-Vitamin E and Its Analogues in Prostate Cancer 516
I. Introduction 517
II. Family Members, Source, and Proper Supplemental Dose of Vitamin E 518
III. General Physiological Function of Vitamin E 519
IV. Vitamin E Absorption and Transport 520
V. alpha-Vitamin E-Binding Proteins 521
A. alpha-Tocopherol Transfer Protein 522
B. alpha-Tocopherol-Associated Protein 522
C. alpha-Tocopherol-Binding Protein 523
D. Other Vitamin E Transport Proteins 523
VI. Vitamin E and Diseases 524
VII. alpha-Vitamin E Function in Prostate Cancer: Clinical Studies 524
VIII. alpha-Vitamin E Function in Prostate Cancer: Animal Studies 529
IX. alpha-Vitamin E in Prostate Cancer: Molecular Mechanism Studies in Cancer Cells 530
A. Cellular Bioavailability of alpha-Vitamin and Ves 530
B. Cell Cycle Arrest and DNA Synthesis Arrest 530
C. Apoptosis 531
D. Signal Pathway 532
E. Invasion, Metastasis, and Angiogenesis 533
X. Summary and Perspectives 533
References 535
Chapter 20: Vitamin E: Inflammation and Atherosclerosis 542
I. Introduction 543
II. Inflammation and Atherosclerosis 544
III. Vitamin E 545
A. Chemical Form and Absorption 545
IV. Animal Studies 546
A. Other Forms of alpha-T and Their Significance 547
B. alpha-T Supplementation in Humans 548
C. Molecular and Cellular Effects of alpha-T 552
V. Intervention Studies 553
VI. Other Forms of Vitamin E 554
A. gamma-Tocopherol 554
B. Absorption and Availability 554
C. gamma-T and Antiinflammatory Effects 555
D. gamma-T and Other Beneficial Effects 555
E. gamma-Tocopherols and Cardiovascular Disease 556
F. gamma-T Supplementation in Humans 558
VII. Tocotrienols 559
VIII. Hypocholesterolemic Effect 560
IX. Antiinflammatory Effects 564
X. Antioxidant Effect 564
XI. Mechanism of Action and Future Direction 565
XII. Conclusion 565
References 566
Chapter 21: Vitamin E in Chronic Liver Diseases and Liver Fibrosis 574
I. Fibrosis in Chronic Liver Diseases 575
II. Oxidative Stress, Chronic Liver Disease, and Liver Fibrosis 577
A. Oxidative Stress in Alcohol-Induced Liver Damage 578
B. Oxidative Stress in Iron-Induced Liver Damage 579
C. Oxidative Stress and Vitamin E in Autoimmune Hepatitis 581
D. Oxidative Stress and Vitamin E in Cholestatic Liver Diseases 581
E. Oxidative Stress in HCV-Related Liver Disease 583
F. Oxidative Stress and Vitamin E in HBV-Related Liver Disease 586
G. Oxidative Stress and Vitamin E in Liver Cirrhosis and Hepatocellular Carcinoma 587
H. Oxidative Stress in Nonalcoholic Fatty Liver Disease 588
References 590
Index 598
Vitamin E
Debbie J. Mustacich*; Richard S. Bruno†; Maret G. Traber*,,‡ * Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331
† Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06269
‡ Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, Oregon 97331
Abstract
The term vitamin E is used to describe eight lipophilic, naturally occurring compounds that include four tocopherols and four tocotrienols designated as α‐, β‐, γ‐, and δ‐. The most well‐known function of vitamin E is that of a chain‐breaking antioxidant that prevents the cyclic propagation of lipid peroxidation. Despite its antioxidant function, dietary vitamin E requirements in humans are limited only to α‐tocopherol because the other forms of vitamin E are poorly recognized by the hepatic α‐tocopherol transfer protein (TTP), and they are not converted to α‐tocopherol by humans. In attempts to gain a better understanding of vitamin E’s health benefits, the molecular regulatory mechanisms of vitamin E have received increased attention. Examples of these mechanisms include: (1) the role of the hepatic α‐TTP in preferentially secreting α‐tocopherol into the plasma, (2) phase I and phase II metabolism of vitamin E and the potential impact for drug–vitamin E interactions, and (3) the regulation of biliary excretion of vitamin E by ATP‐binding cassette protein(s). It is expected that the continued studies of these regulatory pathways will provide new insights into vitamin E function from which additional human health benefits will evolve.
I Introduction
Vitamin E was discovered by Evans and Bishop (1922) as a dietary factor necessary for reproduction in rats. At present, it is among the most commonly consumed dietary supplements in the United States due to the belief that vitamin E, as an antioxidant, may attenuate morbidity and mortality. Despite the frequent use among millions of Americans, the health benefits beyond its classic antioxidant function remain an enigma because nonantioxidant functions have yet to illustrate vitamin E’s required role in human nutrition. Moreover, it is now becoming evident that vitamin E concentrations in humans are tightly regulated such that high doses of vitamin E supplements do not enhance plasma concentrations by more than three‐ to fourfold. Therefore, this chapter seeks to define the forms and isomers of vitamin E, the molecular basis for their differences in biological activity, and the mechanisms responsible for tissue delivery and for the apparently strict regulation of hepatic vitamin E concentrations.
II Vitamin E Structures and Function
Plants synthesize eight different molecules with vitamin E antioxidant activity, including α‐, β‐, γ‐, and δ‐tocopherols and the corresponding four tocotrienols (Fig. 1). The α‐, β‐, γ‐, and δ‐forms differ with respect to the number and position of the methyl groups on their chromanol ring. The tocotrienols have an unsaturated tail containing three double bonds, while the four tocopherols have a phytyl tail (Fig. 1). RRR‐α‐Tocopherol is the naturally occurring form of α‐tocopherol, containing chiral carbons in the R‐conformation at positions 2, 4′, and 8′. However, chemical synthesis of α‐tocopherol results in an equal mixture of eight different stereoisomers (RRR, RSR, RRS, RSS, SRR, SSR, SRS, SSS) with half having position 2 in the S‐conformation. The synthetic vitamin E is called all‐rac‐α‐tocopherol. Position 2 is critical for in vivo α‐tocopherol activity and only the 2R‐forms are recognized to meet human requirements (Food and Nutrition Board and Institute of Medicine, 2000). (Note: For the purposes of this chapter, the term α‐tocopherol will refer to RRR‐α‐tocopherol.)
Vitamin E functions in vivo as a potent peroxyl radical scavenger (Burton et al., 1983). Peroxyl radicals (ROO•) react 1000 times more favorably with α‐tocopherol (Vit E‐OH) than with polyunsaturated fatty acids (RH). The tocopherol’s phenolic hydroxyl group reacts with an organic peroxyl radical to form the corresponding organic hydroperoxide (ROOH) and the tocopheroxyl radical (Vit E‐O•) (Burton et al., 1985).
In the presence of vitamin E: •+Vit E‐OH→ROOH+Vit E‐O•
In the absence of vitamin E: •+RH→ROOH+R•
•+O2→ROO•
The tocopheroxyl radical (Vit E‐O•) reacts with vitamin C (or other reductants serving as hydrogen donors, AH), thereby oxidizing the latter and returning vitamin E to its reduced state (Buettner, 1993).
‐O•+AH→Vit E‐OH+A•
Biologically important hydrogen donors, which have been demonstrated in vitro to regenerate tocopherol from the tocopheroxyl radical, include ascorbate (vitamin C). Importantly, this regeneration of vitamin E by vitamin C has been demonstrated to occur in humans such that cigarette smokers have faster vitamin E turnover that can be normalized by vitamin C supplementation (Bruno et al., 2005, 2006a).
III Absorption, Transport, and Distribution to Tissues
A Vitamin E Absorption
Vitamin E is fat‐soluble and therefore requires all of the processes needed for fat absorption. Specifically, intestinal absorption of vitamin E requires the secretion of pancreatic esterases and bile acids. Indeed, disorders such as cystic fibrosis or cholestatic liver disease that result in the impairment of biliary secretions result in vitamin E deficiency. These secretions are needed for the micellarization of dietary fats, including vitamin E, and the hydrolysis of triglycerides that release free fatty acids. The micelles are taken up by intestinal enterocytes, then vitamin E is subsequently incorporated into chylomicrons, secreted into the lymphatic system, and finally moves into the plasma (Sokol et al., 1983).
B Requirement for Dietary Fat for Absorption
Vitamin E absorption is also dependent on the fat content of food consumed with the vitamin E such that little absorption occurs from vitamin E supplements in the absence of dietary fat (Borel et al., 2001; Bruno et al., 2006b; Hayes et al., 2001).
No studies have been carried out on the absorption of vitamin E naturally occurring in food, but some data are available examining foods fortified with vitamin E. As might be expected from a low fat food, α‐tocopherol absorption from apples fortified with d6‐α‐tocopheryl acetate was minimal, but increased from 10 to 33% with added dietary fat (from 0‐ to 11‐g fat) (Bruno et al., 2006b). Remarkably, vitamin E added in an emulsifier onto the surface of breakfast cereal was highly bioavailable, despite the low fat content of the food, suggesting that the micellarization of the vitamin E is critical for its absorption (Leonard et al., 2004).
Importantly, the various vitamin E forms, such as α‐ and γ‐tocopherols (Meydani et al., 1989; Traber and Kayden, 1989), or RRR‐ and SRR‐α‐tocopherols (Traber et al., 1990a, 1992), have similar apparent efficiencies of intestinal absorption and secretion in chylomicrons. Thus, no discrimination exists between the various vitamin E forms during absorption.
C Requirement for Chylomicron Synthesis
Early observations from studies examining human vitamin E requirements indicated that patients with abetalipoproteinemia, a genetic defect in the lipidation of apolipoprotein B (Wetterau et al., 1992), developed symptoms characteristic of vitamin E deficiency. Interestingly, the few particles that are lipidated do contain detectable amounts of α‐tocopherol and may allow some absorption and delivery of α‐tocopherol to tissues (Aguie et al., 1995).
Circulating chylomicrons undergo triglyceride lipolysis by lipoprotein lipase (LPL). Studies in vitro demonstrated that LPL bound to the cell surface could transfer vitamin E to cells (Traber et al., 1985). Subsequent studies in mice overexpressing muscle LPL demonstrated that lipase effectively delivers vitamin E to muscle (Sattler et al., 1996). Furthermore, some of the newly absorbed vitamin E is transferred to circulating lipoproteins, for example high‐density lipoproteins (HDL), while some remains with the chylomicron remnants. Thus, during the process of...
| Erscheint lt. Verlag | 16.7.2007 |
|---|---|
| Mitarbeit |
Chef-Herausgeber: Gerald Litwack |
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie | |
| Naturwissenschaften ► Biologie ► Biochemie | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Zoologie | |
| Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik | |
| ISBN-10 | 0-08-054906-3 / 0080549063 |
| ISBN-13 | 978-0-08-054906-4 / 9780080549064 |
| Haben Sie eine Frage zum Produkt? |
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