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NCT Acute Studies

NCT Acute Studies. Bromobenzene Herbert 1, 2- Dichlorobenzene Cesta 1, 4- Dichlorobenzene Cesta N-Nitrosomorpholine Boorman Diquat Turnier Monocrotaline Nyska Thioacetamide Hailey Galatosamine Boorman. Today’s Overview. Chemical Mechanism - Rick Irwin

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NCT Acute Studies

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  1. NCT Acute Studies • Bromobenzene Herbert • 1, 2- Dichlorobenzene Cesta • 1, 4- Dichlorobenzene Cesta • N-Nitrosomorpholine Boorman • Diquat Turnier • Monocrotaline Nyska • Thioacetamide Hailey • Galatosamine Boorman

  2. Today’s Overview • Chemical Mechanism - Rick Irwin • Morphology - Gary Boorman

  3. Bromobenzene

  4. Bromobenzene • CYP P450 catalyzed formation of reactive epoxide metabolite – CYP expression predominates around the central vein • quinone metabolites also formed • metabolites react with cellular proteins • detoxification by reaction with GSH • cytosolic GSH depletion • mitochondrial GSH depletion • mitochondrial damage

  5. Bromobenzene • Acute centrilobular necrosis • Rim of hepatocytes immediately adjacent to terminal hepatic venule • Minimal inflammatory infiltrate • Fairly uniform between animals/lobes • Bromobenzene and 1, 2-dichlorobenzene appear similar; 1, 4-DCB - no lesions

  6. Bromobenzene 24-hour Sac • Example of centrilobular hepatocyte degeneration at 75 mg/kg; degenerative hepatocytes are swollen and have pale (rarefied) cytoplasm; note that there is also centrilobular glycogen depletion

  7. Bromobenzene 24-hour Sac • Example of centrilobular hepatocyte necrosis at 250 mg/kg; necrosis is massive coagulative and hemorrhagic effacing large areas of the hepatic parenchyma

  8. N-Nitrosomorpholine • CYP catalyzed hydroxylation at 2’ and 3’ position on morpholine ring • protein and DNA adducts

  9. Hepatotoxicity • an initial wave of apoptosis which peaks at 12 hours but involves only 3-6% of hepatocytes • followed by hepatocellular necrosis which is prominent by 24 hours • no depeltion of GSH

  10. N-Nitrosomorpholine, 300 mg/kg @ 24 hours, Rat # 34

  11. PP Necrosis Hemorrhage THV N-Nitrosomorpholine 300 mg/kg at 24 hours, Rat # 34

  12. N-Nitrosomorpholine • Acute centrilobular necrosis • Mononuclear inflammatory infiltrate • Fairly uniform between animals/lobes • Prominent karyorrhexis of hepatocytes • Prominent hemorrhage

  13. Diquat (dibromide) • widely used bipyridinium herbicide • under goes one electron redox reaction catalyzed by NADPH cytochrome c reductase to produce high levels of ROS • primary lesion reported to be centrilobular necrosis • initial injury not associated with depletion of GSH • characterized by formation of reactive protein carbonyls - aldehydes and ketones

  14. Diquat 30 mg/kg at 24 hours, Rat # 7

  15. Diquat • Acute centrilobular necrosis • At early times clearly demarcated zone of pale hepatocytes • Rim of hemorrhage at margin of lesions • Necrosis secondary to vascular damage and ischemia?

  16. Monocrotaline • requires bioactivation by CYP’s to reactive dehydro-MCT • targets endothelial cells in the sinusoids and central vein • hepatotoxicity characterized by hemorrhage and activation of coagulation system. • may progress to hepatic veno-occlusive disease (HVOD); used as a model for similar human disease • produces caspase dependent apoptosis

  17. Monocrotaline 300 mg/kg at 24 hrs

  18. Monocrotaline 300 mg/kg at 24 hrs

  19. Monocrotaline • Acute Centrilobular Necrosis • Prominent Hemorrhage • Primary Endothelial Injury? • Hepatocellular Injury Secondary to Ischemia? • Diquat and Riddelliine may have similar mechanisms

  20. Thioacetamide • fungicide • CYP2E1 bioactivation to reactive metabolites • hepatocytes primary target resulting in necrosis

  21. Thioacetamide 150 mg/kg @ 4x

  22. Thioacetamide 150 mg/kg @10x

  23. Thioacetamide • Acute centrilobular necrosis • Apoptosis? • Mononuclear Cell Inflammatory Infiltrate • Fairly uniform between animals/lobes

  24. Galactosamine • metabolized to UDP-hexoseamines and UDP-N-acetylhexosamines in hepatocytes and depletion of UTP • causes a transient block in transcription and protein synthesis associated with UTP depletion • accumulation of metabolites inhibit the synthesis of certain critical membrane proteins • increases permeability of gut and potentially absorption of endotoxin • produces oncotic necrosis, caspase dependent apoptosis, and induces oval cell proliferation

  25. Galactosamine, 1500 mg/kg at 24 hours, Rat # 17

  26. THV PP Galactosamine 1500 mg/kg at 24 hours, Rat # 17

  27. Galactosamine • Patchy to Peripotal necrosis • Granulocytes and Mononuclear Cell Infiltrates • Hemorrhage is not prominent

  28. NCT Acute Studies • Very Rich Morphological Data Base • Both Similarities and Differences with chemicals • Bromobenzene and 1, 2-dichlorobenzene appear similar; 1, 4-DCB - Comparison • Diquat, Monocrotaline and Riddelliine Comparison

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