Page 347 - The Toxicology of Fishes

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Liver Toxicity

David E. Hinton, Helmut Segner, Doris W.T. Au,
Seth W. Kullman, and Ronald C. Hardman

CONTENTS
Introduction............................................................................................................................................328
The Liver as a Target Organ..................................................................................................................328
Major Functions of the Liver ................................................................................................................330
Liver Structure .......................................................................................................................................331
Cells of the Liver .........................................................................................................................335
Hepatocytes.........................................................................................................................335
Nonhepatocyte Cells of the Liver ......................................................................................337
Biliary Epithelial Cells and the Intrahepatic Biliary System ............................................337
Putative Stem Cells of Teleost Liver..................................................................................339
Sinusoidal Endothelial Cells ..............................................................................................340
Hepatic Stellate Cells .........................................................................................................341
Interhepatocytic, Perisinusoidal Macrophages...................................................................341
Pigmented Macrophage Aggregates...................................................................................342
Kupffer Cells.......................................................................................................................342
Selected Landmarks of Fish Liver Development..................................................................................343
Specifics of Liver Function....................................................................................................................348
Liver Metabolism................................................................................................................349
Phase I Metabolism: CYP1A .............................................................................................350
Phase I Enzymes Other than CYP1A ................................................................................351
Hepatic Phase II Metabolism .............................................................................................352
Nuclear Receptors in Liver Biology......................................................................................................352
Mammalian Liver Nuclear Receptors ................................................................................353
Fish Nuclear Receptors with an Emphasis on Teleosts.....................................................353
Pregnane X Receptor (PXR) in Fish..................................................................................355
Constitutive Androstane Receptor (CAR) in Fish .............................................................355
Vitamin D Receptor (VDR) in Fish...................................................................................356
Peroxisome Proliferator-Activated Receptor (PPAR) in Fish............................................357
Role of Nuclear Receptors in Bile Acid, Lipid, and Cholesterol Homeostasis................ 358
Summary.............................................................................................................................358
Introduction to Bile Synthesis and Transport........................................................................................359
Bile Synthesis...............................................................................................................................360
Bile Transport...............................................................................................................................361
Fish Studies ..................................................................................................................................362
MDR-Encoded Transporters...............................................................................................362
Organic Anion-Transporting Polypeptides (OATPs)..........................................................362
Multidrug Resistance-Associated Proteins (MRPs)...........................................................363
Functional and Structural Evidence for a BSEP/SPGP.....................................................363
Bile Flow......................................................................................................................................363
Biliary System Toxicity: Mechanistic Considerations..........................................................................364
Related Studies of Biliary Toxicity in Livers of Fishes..............................................................365
Factors Influencing Xenobiotic-Induced Liver Injury...........................................................................367
Cell Interaction.............................................................................................................................368

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