TOXICIOLOGY
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Transcript of TOXICIOLOGY
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TOXICIOLOGYThe Liver
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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.
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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.
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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
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Functional organization of liver
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.
MID ZONAL
Periportal
Centrilobular
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Biotransformation Detoxification Bioactivation
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Chemicals whose metabolites are associated with hepatoxicity
Ethanol Vinyl chloride Acetaminophen Arsenic Carbon tetrachloride
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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 Source of liver
regeneration
NK
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Causes and effect of hepatic damage
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Organic solvent hepatotoxicityXylene Steatosis, fibrosis, necrosis.
Toluene Steatosis, fibrosis, necrosis.
Styrene Steatosis, fibrosis, necrosis.
Acrylonitrile Necrosis.
Carbon disulfide Necrosis.
Isopropanol Necrosis.
Dimethylformamide Necrosis, steatosis.
Trichloroethane Liver tumors, biliary tract tumour.
Methylene chloride Liver tumors, biliary tract tumour.
White spirit Steatosis, fibrosis, necrosis.
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Fatty change (liver) - Steatosis
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Types of hepatic injuries produced by toxicants
Necrosis Steatosis (lipidosis or fatty liver) Cholestasis Cirrhosis (fibrosis) Vascular injury Neoplasm
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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 (Aalanine aminotrasferase) AST (Aspartate aminotrasferase) Irreversible cell injury leads to cellular death.
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NECROSIS APOPTOSISCell swelling. Cell shrinkage.
Leakage of cellular enzyme.
Formation of apoptotic bodies.
Nuclear disintegration. Nuclear fragmentation.
Inflammation. No inflammation.
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Apoptosis Necrosis
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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).
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Lipidosis (Steatosis/fatty liver)
Carbon tetrachloride(lipidosis)
Interfering with fatty acid oxidation.
Inhibition ofMitochondrial
function
Lipoprotein synthesis
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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.
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Bile canaliculi
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Cholestasis
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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
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Gallbladder
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Enterohepatic circulation
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