TOXICIOLOGYThe 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. Metabolism of hormones.

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.

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

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

Biotransformation Detoxification Bioactivation

Chemicals whose metabolites are associated with hepatoxicity

Ethanol Vinyl chloride Acetaminophen Arsenic Carbon tetrachloride

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

Causes and effect of hepatic damage

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.

Fatty change (liver) - Steatosis

Types of hepatic injuries produced by toxicants

Necrosis Steatosis (lipidosis or fatty liver) Cholestasis Cirrhosis (fibrosis) Vascular injury Neoplasm

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.

NECROSIS APOPTOSISCell swelling. Cell shrinkage.

Leakage of cellular enzyme.

Formation of apoptotic bodies.

Nuclear disintegration. Nuclear fragmentation.

Inflammation. No inflammation.

Apoptosis Necrosis

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).

Lipidosis (Steatosis/fatty liver)

Carbon tetrachloride(lipidosis)

Interfering with fatty acid oxidation.

Inhibition ofMitochondrial

function

Lipoprotein synthesis

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.

Bile canaliculi

Cholestasis

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

Gallbladder

Enterohepatic circulation