Drug-Induced Hepatotoxicity Contributors S. Anuras, M.Z. Badr, A.S. Basile, S.A. Belinsky, L.M. Blendis R.G. Cameron, J.G. Conway, F.A. de la Iglesia, M.U. Dianzani E. Farber, G. Feuer, RJ. Fingerote, P.E. Ganey, A.K. Ghoshal K.G. Ishak, Y. Israel, E.A. Jones, K. Kitani, CD. Klaassen J.S. Leeder, G.A. Levy, I.R. Mackay, D.K. Monteith, A.B. Okey B.K. Park, M. Pirmohamed, W.F. Pool, E.A. Roberts, E. Rubin R.W. Sallie, D.C. Snover, R.G. Thurman, F. Trevisani, D.H. Van Thiel R.R. Varma, R.M. Walker, J.B. Watkins III, P.G. Welling T.F. Woolf, H.J. Zimmerman, M.J. Zuckerman Editors R.G. Cameron, G. Feuer, and F.A. de la Iglesia With a Foreword by M. James Phillips Springer
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Drug-Induced HepatotoxicityF. Prevention 287 References 288 CHAPTER 13 Pediatric Hepatic Drug Reactions E.A. ROBERTS 293 A. Classification of Drug Hepatotoxicity 293 B. Specific Drugs
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Drug-InducedHepatotoxicityContributors
S. Anuras, M.Z. Badr, A.S. Basile, S.A. Belinsky, L.M. BlendisR.G. Cameron, J.G. Conway, F.A. de la Iglesia, M.U. DianzaniE. Farber, G. Feuer, RJ. Fingerote, P.E. Ganey, A.K. GhoshalK.G. Ishak, Y. Israel, E.A. Jones, K. Kitani, CD. KlaassenJ.S. Leeder, G.A. Levy, I.R. Mackay, D.K. Monteith, A.B. OkeyB.K. Park, M. Pirmohamed, W.F. Pool, E.A. Roberts, E. RubinR.W. Sallie, D.C. Snover, R.G. Thurman, F. Trevisani, D.H. Van ThielR.R. Varma, R.M. Walker, J.B. Watkins III, P.G. WellingT.F. Woolf, H.J. Zimmerman, M.J. Zuckerman
Editors
R.G. Cameron, G. Feuer, and F.A. de la Iglesia
With a Foreword by M. James Phillips
Springer
Contents
CHAPTER 1
Orientation in Liver Toxicity by DrugsE. FARBER. With 1 Figure 1
A. Introduction 1B. Agents and Processes 1C. Responses to Injury as Multitier or Multigrid Patterns 2
I. Quantitative Versus Qualitative Changes 3II. Patterns of Liver Toxicity 4
1. Tier One: Patterns of Interactionsof Agents with Liver 4
2. Tier Two: Patterns of Biological Responsesto Cell Injury 8
3. Tier Three: Cellular and Intracellular Responses 104. Tier Four: Cellular and Tissue Physiology 19
D. Conclusion 21References 21
CHAPTER 2
Clinical Studies and Role of Necrosis in HepatotoxicityR.G. CAMERON and L.M. BLENDIS. With 7 Figures 25
A. Zonal Necrosis as a Response to Acetaminophen 25I. Zonality: Specific Hepatocytes Die as a Group 25
II. Ethanol Plus Acetaminophen:Extension of Zone of Necrosis 28
III. Constitutive Bases of Zonal Responses 301. Perivenous Localization
VI. Peroxisomes 57E. Biochemical Pathology of Subcellular Changes 59
I. Cell Respiration 59II. Protein Metabolism 60
III. Lipid Metabolism 61IV. Bile Secretion 62
F. Latent Hepatotoxicity Models 63G. Conclusions 64References 65
CHAPTER 4
Molecular Biology of Hepatic Drug ReactionsR.W. SALLIE and E.A. JONES. With 6 Figures 75
A. Introduction 75B. General Considerations 75C. DNA Damage 77
I. Drugs and DNA Metabolism 77II. DNA Replication and Repair Pathways 78
D. Inhibition of DNA Replication 79I. Inhibition of DNA Polymerases 79
II. Inhibition of DNA Ligase 80
Contents XV
III. Chain Termination 81IV. Inhibition of DNA Repair 81V. Alterations in Purine/Pyrimidine Metabolism 83
VI. Alterations in DNA Processing Post Synthesis 83E. Damage to RNA 84F. Interference with Protein Synthesis 85G. Apoptosis 86H. Future Developments 92I. Summary and Conclusions 93
References 94
CHAPTER 5
In Vitro Models of Liver ToxicityR.G. THURMAN, P.E. GANEY, S.A. BELINSKY, J.G. CONWAY,
and M.Z. BADR. With 4 Figures 99
A. Introduction 99I. Metabolism of Foreign Compounds
Can Cause Zone-Specific Hepatotoxicity 99II. Advantages and Disadvantages of Whole Cell Models 100
B. Techniques Used to Study Zone-Specific Hepatotoxicityin the Isolated Perfused Liver 101
I. Metabolite Measurements in Tissue and Perfusate 103II. Microlight Guides 104
III. Miniature Oxygen Electrodes 105IV. Trypan Blue Exclusion 106
C. Applying In Vitro Models to the Study of Liver Toxicology 106I. Monooxygenation in Periportal and Pericentral Zones
of the Liver Lobule 106II. Conjugation Reactions in Periportal and Pericentral
Regions of the Liver Lobule 1071. Sulfation 1072. Glucuronidation 109
III. Oxygen as a Determinantof Zone-Specific Hepatotoxicity I l l
D. Conclusions 113References 113
CHAPTER 6
Cytochromes P450 and Liver InjuryJ.S. LEEDER and A.B. OKEY. With 4 Figures 119
A. Drug Biotransformation, Cytochromes P450 and the Liver 119I. Drug Biotransformation by the Liver 119
II. General Drug Biotransformation Processes 119
XVI Contents
III. Phase I Reactions 120IV. Introduction to the Cytochromes P450 120
B. Cytochromes P450 and Drug Biotransformation 121I. Human Hepatic Cytochromes P450 121
II. Sources of Variability in P450 Expression and Activity . . . . 1251. P450 Genetics and Polymorphisms 1262. P450 Induction 1273. P450 Inhibition 1294. Liver Disease: Effects on Drug Biotransformation 130
II. Reaction Mechanism 130III. Drug Biotransformation and Drug Toxicity 132
1. Cytochrome P450 and Bioactivation 1322. Activation/Detoxification Balance 1323. "Probe Drugs" for Determining P450 Activities
in Humans In Vivo 134C. Mechanisms of P450-Mediated Liver Injury 135
II. P450s as Targets of Immune Effectors 138D. Specific Drugs/P450s and Liver Injury 139
I. Acetaminophen 139II. Halothane 141
III. Tienilic Acid 142IV. Dihydralazine 143V. Diclofenac 144
E. Conclusions 144References 145
CHAPTER 7
Mechanisms of Drug-Induced CholestasisJ.B. WATKINS III and C D . KLAASSEN 155
A. Definition of Cholestasis 155B. Mechanisms of Canalicular Bile Formation 156
I. Transport of Bile Acids 156II. Transport of Inorganic Ions and Glutathione 157
III. Other Mechanisms 157C. Mechanisms of Cholestasis 158
I. Alterations in Basolateral Membrane Function 158II. Alterations in Canalicular Membrane Function 158
III. Alterations in Intracellular Events 1591. Binding to Intracellular Proteins
and Conjugation Enzymes 1592. Cytoskeleton 159
Contents XVII
IV. Permeability Changes in the Biliary Tree 1601. Altered Permeability of the Junctional Complex 1612. Altered Permeability of the Canalicular Membrane 1613. Alterations in Membrane Proteins 1624. Alterations in Membrane Composition and Function . . . 164
D. Drugs and Other Chemicals Inducing Cholestasis 165I. a-Naphthylisothiocyanate 165
II. Androgenic and Estrogenic Steroids 166III. Bile Acids 168IV. Chlorpromazine and Other Phenothiazines 169V. Cyclosporine 170
VI. Miscellaneous Cholestatic Agents 170References 171
CHAPTER 8
Fatty Liver and DrugsM.U. DIANZANI. With 1 Figure 185
A. General Mechanisms for Fatty Liver 185B. Drugs Provoking Fatty Liver 187
I. Drugs Provoking Fatty Liver by IncreasingFFA Supply to the Liver 187
II. Drugs Provoking Fatty Liverby Intrahepatic Mechanisms 1881. Drugs Increasing Intrahepatic FFA Synthesis 1882. Drugs Provoking Fatty Liver by Decreasing
III. Drugs Decreasing Fat Infiltration in the Liver 200References 202
CHAPTER 9
Choline Deficiency: An Important Modelfor the Study of HepatotoxicityA.K. GHOSHAL. With 2 Figures 211
A. Introduction 211B. Hepatotoxicity by Dietary Manipulation - Not by Addition
but by Depletion 212C. Absence of Choline in an Otherwise Complete Diet -
An Excellent Model for the Study of Liver Cell Deathand Liver Cancer 213
XVIII Contents
I. Choline Deficiency Model and Cell Death 215II. Choline Deficiency and Liver Cancer 216
D. Lipotrope Deficiency Versus Choline Deficiency 217E. Step by Step Development of Liver Aberration 217F. Hypothesis of Choline Deficiency Induced Hepatocarcinoma 218G. Conclusions 218References 218
CHAPTER 10
Immune Mechanisms and Liver ToxicityI.R. MACKAY. With 3 Figures 221
A. Introduction and Overview of Drug-Mediated Hepatotoxicity 221B. Functional Aspects of the Immune System 222
I. Immune Repertoire 222II. Major Histocompatibility Complex 223
III. Afferent Limb of the Immune Response 224IV. Efferent Limb of the Immune Response 225V. Regulation and Dysregulation of Immune Responses 226
C. Genetic Determinants of Adverse Drug Reactions 227D. Liver in Relation to Adverse Drug Reactions 228
I. Intrahepatic Metabolism of Drugsby Microsomal Enzymes 2281. Cytochrome P450 Oxidases (CYP450) 2282. UDP Glucuronosyl Transferases 2283. Carboxyl Esterases 228
II. Intrahepatic Immune Processes 2291. Initiation of Immune-Mediated Drug Reactions
in the Liver 2292. Regulatory and Dysregulation
of Intrahepatic Immune Reactions 229III. Infrequency of Hepatic Hypersensitivity
Drug Reactions 230IV. Immunopathology of Hepatic Hypersensitivity
Drug Reactions 230V. Drug-Altered Neoantigen - The Halothane Paradigm 232
1. Halothane Hepatitis 2322. Immunological Investigations of Halothane Hepatitis . . . 2333. Detection of Antibodies to TFA Conjugates 233
VI. Native Liver Antigens - The Liver-Kidney Microsomal(LKM) System 2341. Hepatitis with Anti-LKM-2 2352. Identification of LKM as Cytochrome P450 Species 235
Contents XIX
3. Antibodies to CYP 1A2 in Drug-Induced Hepatitis 2364. Inhibition of Enzyme Function by Anti-LKM 2375. Origins of Anti-LKM Reactivity ' 237
VII. Drug-Induced Hepatitis with Reactions to Autoantigens . . . 238E. Experimental Models of Drug-Induced Immune-Mediated
Disease 239F. Laboratory Investigation of Immune-Mediated
Hepatic Drug Reactions 240I. General Laboratory Investigations 240
II. Drug-Specific Immunological Investigations 2401. Detection of T-Cell-Mediated Reactions 241
III. Pharmacological Idiosyncrasy 242References 242
CHAPTER 11
Hepatic EncephalopathyA.S. BASILE 249
A. Introduction 249I. Clinical Manifestations of Hepatic Encephalopathy 249
II. Neuropathological Changes in Hepatic Encephalopathy . . . 2511. Anatomy 2512. Electrophysiology 251
B. Involvement of Neurotoxins in the Pathogenesisof Hepatic Encephalopathy 252
I. Ammonia 2531. Glial Interactions 2532. Electrophysiological Changes 2543. Changes in Oxidative Metabolism 2564. Summary 256
II. Synergistic Neurotoxins 257C. Neurotransmitter Involvement in the Pathogenesis
of Hepatic Encephalopathy 258I. y-Aminobutyric Acid 258
XVIII. Amiodarone 310XIX. Nitrofurantoin 311XX. Retinoids 311
XXI. Azathioprine 311XXII. Cocaine 312
References 312
CHAPTER 14
Reye's SyndromeR.R. VARMA 323
A. Introduction 323B. Clinical Features 324C. Laboratory Features 326D. Diagnostic Criteria for Population Surveys 327E. Liver Morphology 328F. Brain Morphology 328G. Liver Histology and Electron Microscopy in Reye's Syndrome . . . . 329H. Pathophysiology 330I. Aspirin and Reye's Syndrome 332J. Animal Models 334
K. Reye's Syndrome in Adults 335L. Treatment 335M. Sequelae 336References 337
CHAPTER 15
Drug Hepatotoxicity in the ElderlyK. KITANI. With 7 Figures 341
A. Introduction 341B. Clinical Information 341
I. Idiosyncratic Hepatotoxicity. The Swedish Experience 341II. Dose-Dependent Hepatotoxicity 343
XXII Contents
C. Age-Related Alterations in Hepatic Detoxifying Functions:Discrepancies Between Human and Animal Data 343
I. Phase I Drug Metabolism 344II. Phase II Metabolism 346
1. Glucuronidation and Sulfation:Acetaminophen Conjugation 346
2. Glutathione S-Transferases 347III. Oxidant and Antioxidant Variables 350
D. Morbidity and Frailty as Major Factors for Lowered DrugClearances in the Elderly: A Possible Role in Hepatotoxicity 353
E. Adverse Drug Reactions in the Liver in Old Animals:Mini Review 354
I. Hepatocyte Susceptibility to Chlorpromazineand Erythromycin Estolate 355
II. Acetaminophen Hepatotoxicity: An Exampleof Variability of the Results in Studies Using Rodents 355
III. Ethanol Metabolism in the Liver and Its Hepatotoxicity:Another Controversy 358
IV. Hepatotoxicities by Other Toxicants 361F. Conclusions and Suggestions for Future Studies 361References 362
CHAPTER 16
Effect of Liver Disease on Drug Metabolism and PharmacokineticsP.G. WELLING and W.F. POOL. With 6 Figures 367
A. Introduction 367B. Function and Structure of the Liver 368C. Types and Severity of Liver Disease 369
I. Changes in Hepatic Function 369II. Changes in Hepatic Vasculature 369
III. Changes in Renal Function 370IV. Ascites 370
D. Pharmacodynamic Factors 370E. Pharmacokinetic Factors 371
I. Linear Pharmacokinetic Models 3711. One-Compartment Model, Intravenous Dosing 3712. First-Order Absorption and Elimination 3733. Repeated Dosing with Linear Pharmacokinetics 374
II. Nonlinear Pharmacokinetic Models 376
Contents XXIII
III. Impact of Liver Disease 3771. Distribution Volume 3792. Elimination Half-Life 3793. Protein Binding 3804. Presystemic Clearance 380
F. Markers of Liver Disease Relevant to Drug Metabolismand Pharmacokinetics 381
G. Examples of Effects of Liver Disease on the Pharmacokineticsof Some Drug Therapeutic Classes 382
I. Cardiovascular Agents 383II. Drugs Acting on the Central Nervous System 384
III. Antimicrobial Agents 385IV. Other Drugs 386
H. Conclusions 387References 388
CHAPTER 17
Liver Reactions to TacrineT.F. WOOLF, W.F. POOL, R.M. WALKER, and D.K. MONTEITH.
With 2 Figures 395
A. Introduction 395B. Clinical Experience 395C. Metabolism of Tacrine in Humans 397D. Preclinical Toxicology 399E. Metabolism of Tacrine in Animals 401F. Cytotoxicity Studies 402G. In Vitro Metabolism Studies 403H. Conclusions 405References 406
CHAPTER 18
Mechanisms of HypertransaminemiaM. PIRMOHAMED and B.K. PARK. With 7 Figures 411
A. Introduction 411B. Overview of Liver Transaminase Monitoring 411
I. Significance of the Different Tests Used to MonitorLiver Function 411
II. Spectrum of Drug-Induced Hepatotoxicityand Hypertransaminemia 413
XXIV Contents
III. Clinical Correlates of Transaminase Measurement 4141. Sensitivity and Specificity of Hypertransaminemia 4142. Correlation Between Severity of Hepatic Injury
and Degree of Hypertransaminemia 4153. Clinical Significance of Minor Degrees
of Hypertransaminemia 416C. Classification of the Causes of Hypertransaminemia 419D. Mechanisms of Acute Hepatic Injury
Leading to Hypertransaminemia 419I. Role of Drug Metabolism 419
II. Evidence for the Formation of Chemically ReactiveMetabolites 421
III. Acute Chemical Hepatotoxicity 4221. Acetaminophen Hepatotoxicity 4222. Carbon Tetrachloride Hepatotoxicity 424
C. Female Sex Hormones and the Contraceptive Steroids 551I. Estrogenic Hormones and Related Drugs 551
II. Progestational Steroids 552III. Adverse Effects of Contraceptive Steroids on the Liver . . . 553IV. Syndrome of Contraceptive Steroid Jaundice 554
1. Clinical Features 5542. Biochemical Features 5543. Histologic Characteristics 5544. Prognosis 5545. Susceptibility 554
V. Tumors Associated with Oral Contraceptives 5551. Hepatocellular Adenoma 5552. Focal Nodular Hyperplasia 5583. Hepatocellular Carcinoma 558
VI. Vascular Lesions 5601. Effect on Hemangiomas and Related Lesions 5602. Sinusoidal Dilatation 5603. Peliosis Hepatis 5604. Hepatic Vein Thrombosis 5615. Rupture of the Liver 5626. Other Vascular Changes 563
VII. Disturbed Porphyrin Metabolism 563VIII. Mechanisms of Injury by Contraceptive Steroids 563
IX. Cholelithiasis 564D. Drugs Related to Sex Hormones 565
I. Antiestrogens 5651. Clomiphene 5652. Cyclofenil 5653. Tamoxifen 565
Contents XXIX
II. Antihypophysial Drugs 5651. Danazol 5652. Octreotide 566
E. Glucocorticoids 566F. Oral Hypoglycemic Agents 566
I. Sulfonylureas 566II. Clinical Syndrome 567
III. Prognosis 568IV. Biguanide 569V. Other Oral Hypoglycemic Agents 569
G. Antithyroid Drugs 569I. Form of Injury 570
II. Clinical Features 570III. Prognosis 570IV. Mechanism 571V. Comment 571
References 571
CHAPTER 24
Hepatotoxicity of Immunomodulating AgentsR.J. FINGEROTE and G.A. LEVY 581
A. Introduction 581B. Immunostimulatory Agents 582
I. Classification 5821. Immune-System-Derived Biologicals 5832. Immunostimulatory Pharmaceutical Agents 583
II. Hepatotoxicity of Specific Immunostimulatory Agents 5831. Interleukin-2 5832. Interferons 585
C. Immunosuppressive Agents 588I. Classification 588