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Hepatic Toxicity UNC School of Public Health

Hepatic Toxicity UNC School of Public Health. Friday - Nov. 3 Introduction to the liver Gary Boorman, NIEHS Monday - Nov. 6 Molecular aspects of liver injury Dr. Robert Sills, NIEHS Wednesday - Nov. 8 Biochemistry of hepatic injury Dr. LeCluyse, CellzDirect, Inc.

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Hepatic Toxicity UNC School of Public Health

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  1. Hepatic Toxicity UNC School of Public Health Friday - Nov. 3 Introduction to the liver Gary Boorman, NIEHS Monday - Nov. 6 Molecular aspects of liver injury Dr. Robert Sills, NIEHS Wednesday - Nov. 8 Biochemistry of hepatic injury Dr. LeCluyse, CellzDirect, Inc. Friday Nov. 10 Acute Responses to Hepatic Injury Dr.Rich Miller GSK Monday, Nov 13 Chronic effects of hepatic injury Dr. Amy Brix, EPL

  2. Why is the Liver so Important in Toxicology? Hepatotoxicity is the major reason for rejecting new drugs in clinical trials and withdrawal of drugs already in use Major metabolic organ Hepatotoxicity is quite common Cirrhosis - One of top ten causes of death Model for cancer mechanisms

  3. Liver in Toxicogenomics The liver is currently the major tissue for Toxicogenomics > 6,200 references on gene expression and liver in last three years Easily accessible large parenchymal organ Model for defining toxic responses Gene changes reflect systemic responses

  4. Lecture Outline Role of the liver Anatomy of the liver Organization of the liver Cells of the liver Rodent diseases affecting liver

  5. Liver is Complex Organ Largest organ in body 1500 g in humans (2% of BW) 15 g in male rat (4% of BW) 1.5 g in male mouse (6% of BW) 25% of cardiac output 2 L/Minute in 70 kg Human Source of most plasma proteins Interface between food and energy needs Largest source of fixed macrophages Marked circadian rhythm

  6. Role of the Liver Processes, dietary proteins, carbohydrates, lipids Stores and releases energy Exports Glucose from glycogen Exports Acetoacetate from fatty acids Detoxification Endogenous & Exogenous compounds Oxidation and reduction Conjugation and hydrolysis Important role in vitamins Active synthesis of some forms of B vitamins Proteins for transport of vitamins Retinoid storage and metabolism

  7. Role of the Liver Acute Phase Response Transient increase or decrease in plasma proteins Systemic response to local injury Phagocytosis of particulates Critical location with blood flow from GI tract Central role in cholesterol homeostasis Critical for iron, zinc and copper metabolism

  8. Maronpot, Pathology of the mouse. 1999

  9. Maronpot, Pathology of the mouse. 1999

  10. Lobe Differences with Acetaminophen 50, 150, 1500, and 2000 mg/kg For each rat evaluated both left (L) and median (M) lobe Yellow highlights dose Pink highlights Left Lobe

  11. Acute Phase Proteins show remarkable Lobe dichotomy Ttr = Transthyretin Fgb = Fibrinogen, beta Ahsg = alpha-2-HS glycoprotein Tf = transferrin Significantly DOWN regulated Median (M) lobe Significantly UP regulated Left (L) lobe WHY?

  12. Lobe variability Gene expression Copper distribution (R > L) Cancer (R > L) Cirrhosis of right lobe Hypertrophy of left lobe Cirrhosis of left lobe No Hypertrophy of right lobe

  13. Why are there lobe differences? Umbilical blood flows to left lobe (Fetus) Right and median lobes receive portal blood Left better oxygenated during development Left more directly exposed to maternal toxins Differential portal flow to lobes (Adult) Blood from stomach to left lobe Blood flow from colon to right lobe Colonic cancer metastatic more to right lobe Blood flow from spleen to left lobe Contains hepatic growth factors May explain cirrhosis and hypertrophy

  14. Organization of Liver Hepatic plates with bile canicular system Dual blood supply 75% portal vein (low in oxygen) 25% hepatic artery (high in oxygen) Blood collects in hepatic vein

  15. Tissues and Organs:a text of scanning electron microscopy, Kessel, RG and Kardon,RH, 1979

  16. Approximately 1 million classic lobules per liver

  17. Rappaport Unit Zone 1 (central or periportal) Largest hepatocytes More mitochondria More granular ER Glycogen metabolism Glucuronidation of xenobiotics Formation of plasma proteins Best oxygenated Highest concentration of bile salts More Kupffer cells

  18. Portal “triad” (zone 1) hepatic artery (1-2) portal vein (1) bile duct (1-2) lymphatics nerves connective tissue-collagen type I Pathology of the Liver, MacSween RNM et al, 2002

  19. Glucose-6-phosphatase Teutsch, et al. 1999. Hepatology 29:494-505

  20. Allyl Alcohol-Induced Necrosis in Zone 1 PP THV THV PP

  21. Rappaport Unit Zone 3 (More peripheral - Terminal Hepatic Venule) (most commonly Centrilobular) Smaller hepatocytes Fewer mitochondria More agranular ER Fat and pigment storage Reductase reactions Enzyme induction may occur More susceptible to anoxia

  22. Acetaminophen Necrosis in Zone 3 1 2 3 THV

  23. Sometimes lesions are patchy involving more than a lobule

  24. Rat caudate lobe with resin in the portal vein demonstrating three dimensional units Bhunchet and Wake, Hepatology 27:481-487, 1998-487, 1998

  25. Vascular damage following acetaminophen (MRI image) Malarkey, Ryan, Johnson, Maronpot, 2004

  26. Temporal Aspects are also important in the liver

  27. Gene Expression for Metallothionein 1a varies by time during the 24 hour day CT times; light 0 - 12: Dark 12-24

  28. Phase I enzymes that vary by age in the rat

  29. Hepatic CYP expression varies with age of rat What might this mean for a study where rats are exposed 2 years ?

  30. Hepatic dimensions • Liver is a heterogeneously complex organ Space • Variation by lobe • Zones within lobes • Three-dimensional parenchymal units Time • Variation by time of day • Variation by age

  31. Heterogeneity of liver • Epithelial Cells • Hepatocytes • Cholangiocyes • Mesenchymal cells • Kupffer cells • Endothelial cells • Stellate cells • Other Hepatic components • Smooth muscle cells (blood vessels) • Mesothelia (capsule) • Nerves (unmyelinated) • Neuroendocrine cells • Hematopoeitic cells • Extracellular matrix • 5-10% of liver is collagen

  32. Heterogeneity of liver • Hepatocytes (60%) • Biliary epithelium (3-5%) • Endothelia (20%) • sinusoids • blood vessels (arteries and veins) • lymphatics • Kupffer cells (15%) • Hepatic stellate cells (5 -%) • Lymphocytes (Pit cells)

  33. 5 major players

  34. Hepatocytes • 80% of mass; 60% of cell numbers • SER and RER (15% of cell volume) • Free ribosomes • Golgi complex • Lysosomes (~ 30 per cell) • Peroxisomes / microbodies (~ 500 per cell) • Mitochondria (1000 per cell) • Cytoskeleton (microfilaments, intermediate filaments, microtubules) • Glycogen • Produces bile (~ 15 ml per kg per day)

  35. Lobular Heterogeneity: The Streaming Liver Pathology of the Liver, MacSween RNM et al, 2002

  36. Gene expression varies along the hepatic plate What might happen to Glutamine synthetase (GS) Transcript levels with zone 3 necrosis?

  37. Endothelial Cells 20% of liver cells, 3.3% of protein content Discontinuous individual cells/fenestrated Sieve plates - clustered fenestrate Direct access of blood to hepatocytes Gives rise to vascular tumors Vinyl chloride hemangiosarcomas - human carcinogen

  38. Sinusoidal endothelial cells Fenestrations Tissues and Organs: a text of scanning electron microscopy, Kessel, RG and Kardon,RH, 1979

  39. Pathology of the Liver, MacSween RNM et al, 2002

  40. Kupffer Cells 15% of liver cell population, 2.5% of liver protein Precursors arise from circulating monocytes Major component of fixed macrophage system Ingest particles May contribute to liver disease Mediators of inflammation (TNF-alpha)

  41. Liver showing hepatocytes (H), Kupffer cells (KC), endothelial cells (EC) and stellate cells (SC)

  42. Stellate Cells 5% - 8% of all parenchymal cells Vitamin A storage and metabolism Significant source of collagen, hepatic fibrosis Major player in hepatic regeneration Control microvascular tone Ito cell tumors in mice

  43. Hepatic Stellate Cells (HSC) • Periportal (PP) • small HSCs • perisinusoidal processes • small volume of lipid droplets • Midzone • elongated • large volume of lipid • intense desmin • Central vein (CV) • elongated & IC processes • vitamin A and desmin reduced

  44. Tissues and Organs: a text of scanning electron microscopy, Kessel, RG and Kardon,RH, 1979

  45. Hepatic Stellate cells wrap around Endothelial Cells

  46. Biliary cells 3% to 5% of liver cell population Form approximately 2 km of tubules Tight junctions isolate lumen Modifies bile Active in secretion and absorption Effective communicator with other cells Contains numerous transporters

  47. Prevalence of Rodent Pathogens that affect Liver Helicobacter Species 31% Epidemic Diarrhea of Infant Mice EDIM Virus 15% Mouse Hepatitis Virus 14% Rat Parvo Virus 6% Dr. Lila Riley (University of Missouri Diagnostic Laboratory)

  48. Source of Rodent Pathogens Transfer of transgenic mice Sharing of biological specimens Other animals in colony Feral animals Animal care personnel & visitors Dr. Lila Riley (University of Missouri Diagnostic Laboratory)

  49. Acute Hepatotoxicity Dr. Sills (This Monday) Molecular biology of hepatic injury Dr. Sills will assume that you know hepatic lobules before lecture…. Liver structure is also critical for Dr. Millers lecture the following Friday

  50. Thanks to Dave Malarkey for several new slides

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