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TOXICIOLOGY

TOXICIOLOGY. The Liver. Vital functions of Liver. Carbohydrate storage and metabolism. Storage of vitamin A and D. Biosynthesis of glycogen, albumin, globulin, steroids, blood-clotting factors and angiotensinogen. Biotransformation and excretion of xenobiotics. Fat metabolism.

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TOXICIOLOGY

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  1. TOXICIOLOGY The Liver

  2. Vital functions of Liver • Carbohydrate storage and metabolism. • Storage of vitamin A and D. • Biosynthesis of glycogen, albumin, globulin, steroids, blood-clotting factors and angiotensinogen. • Biotransformation and excretion of xenobiotics. • Fat metabolism. • Metabolism of hormones.

  3. Vital functions of Liver • Synthesis of bile acids/salts that aid in digestion of fats. • Formation of urea from amino acids. • Transport & storage of lipids, metals such as iron, copper, Zinc, and cadmium. • Phagocytosis of micro-organism and other foreign bodies. • Degradation of hemoglobin (bilirubin) and root of elimination for bile pigments & hemoglobin metabolites.

  4. 1. portal triad 2. lobule 3. central vein 4. bile canaliculi 5.common bile duct 6. hepatic portal vein 7. hepatic artery 8. hepatocyte plate (with hepatocytes) 9.sinusoids

  5. Functional organization of liver MID ZONAL Periportal • Periportal:High respiratory enzyme activity & glutathione contents. Take up more bile acid & secrete more bile constituents. Detoxification of ammonia to urea. • Midzonal region: High regenerative activity • Centrilobular: High concentration of P450 enzyme & low concentration of glutathione. Centrilobular

  6. Biotransformation • Detoxification • Bioactivation

  7. Chemicals whose metabolites are associated with hepatoxicity • Ethanol • Vinyl chloride • Acetaminophen • Arsenic • Carbon tetrachloride

  8. Reticuloendothelial system • Kupffer cell • Lipocytes (Ito cell) • Endothelial cell • Pit cell • Oval cell or stem cells Hepatocytes are characterized by their abundant Endoplasmic reticulum, mitochondria and secretory organelles. Hepatic Sinusoid NK Source of liver regeneration

  9. Causes and effect of hepatic damage

  10. Organic solvent hepatotoxicity

  11. Fatty change (liver) - Steatosis

  12. Types of hepatic injuries produced by toxicants • Necrosis • Steatosis (lipidosis or fatty liver) • Cholestasis • Cirrhosis (fibrosis) • Vascular injury • Neoplasm

  13. Hepatocyte death& necrosis • Hepatocytes death can be focal, zonal (Centrilobular, midzonal,periportal) or massive (Panlobular). • Cell life span is about 6 months. • Hepatocytes die by either necrosis or apoptosis. • ALT (Aalanineaminotrasferase) • AST (Aspartateaminotrasferase) • Irreversible cell injury leads to cellular death.

  14. Apoptosis Necrosis

  15. Lipidosis (Steatosis/fatty liver) • It is characterized by increase in hepatic lipid content to greater than 5% of liver weight. • Liver enlarges due to accumulation of lipid and triglycerides. • The lipid appear as vacuoles in hepatic cytoplasm, often displacing the nucleus of the cell. • Factors (obesity, alcoholisms, protein deficient diet).

  16. Lipidosis (Steatosis/fatty liver)

  17. Cholestasis • Accumulation with in the bile canliculi of bile pigments and other products that restrict the normal flow of bile. • Liver retains bile salts and bilirubin which can lead to jaundice. • Cholestasis that is toxicant induced can be reversible or chronic. • Canalicular cholestasis include the presence of bile within the hepatocytes and canalicular spaces.

  18. Bile canaliculi

  19. Cholestasis

  20. Cholestasis • Bile salts are strong surfactants, their accumulation with in hepatocytes can produce cell membrane injury. • Toxicants that can produce canalicular cholestasis: • Anabolic steroids, cyclosporin, phallodin, 1,1dichloroethylene, chlorpromazine, organic arsenicals, erythromycin, oral contraceptive

  21. Gallbladder

  22. Enterohepatic circulation

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