Hepatotoxicity

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Hepatotoxicity

• Dr. Jena Hamra

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Liver Physiology

• Liver lobule
• Hexagonal
• Portal triad
• Portal vein
• Hepatic arteriole
• Bile duct

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Liver Physiology

• Acinus
• Zones between 2 central veins
• Zone 1
• Closest to portal triad
• High oxygen levels
• High glutathione levels
• Zone 2
• Zone 3
• Near central vein
• Low oxygen levels
• High CP450 levels

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Liver Physiology

• Sinusoids
• Vascular channels between cords of hepatocytes
• Cell types
• Endothelial cells
• Pores
• Kupffer cells
• Ito cells

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Liver Function

• Nutrient biosynthesis and storage
• Filtration of particulates
• Protein synthesis
• Clotting factors
• Biotransformation
• Bile formation

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Bile Formation

• Bile
• Bile salts
• Glutathione
• Cholesterol
• Bilirubin
• Active transport of bile salts
• Mdr transporter
• Multiple organic anion transporter
• Transport of metal ions

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Liver Injury

• Fatty liver
• Abnormal accumulation of fat in hepatocytes
• Causes
• Excess synthesis of lipids
• Oversupply of free fatty acids to liver
• Decreased secretion of lipoproteins from liver

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Liver Injury

• Hepatocyte death
• Necrosis
• Apoptosis
• Pattern of cell death
• Focal
• Zonal
• Lobular

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Liver Injury

• Cholestasis
• Suppression or stoppage of bile flow
• Blockage of bile ducts
• Structural
• Chemical induced
• Impaired secretion of bile component
• Cirrhosis
• Deposition of collagen throughout liver
• Chronic chemical injury

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Liver Injury

• Hepatitis
• Inflammation of liver
• Infectious or chemical induced
• Carcinogenesis
• Hepatocellular
• Angiosarcomas

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Mechanisms of Liver Injury

• Accumulation in liver tissue
• Lipophilic compounds
• Active uptake systems
• Bioactivation
• Reactive metabolite formation
• Inflammation
• Migration of inflammatory cells
• Activation of Kupffer cells

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Mechanisms of Liver Injury

• Cholestasis
• Tight junction leakage
• Disruption of cytoskeleton integrity
• Decrease in bile acid uptake
• Reactive chemicals in pericanalicular area
• Disruption of cytoskeleton
• Microcystin
• Mitochondrial damage

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Carbon Tetrachloride

• Formation of reactive metabolites

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Bromobenzene

• Formation of reactive epoxides
• Centrilobular necrosis

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Acetaminophen

• Formation of reactive electrophilic intermediate
• Centrilobular necrosis

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Halothane

• Formation of reactive metabolites
• Free radical
• Reactive electrophile
• Centrilobular necrosis