PHRD5935 Pharm/Tox Lecture 10 - Mechanisms of Toxicity and Cellular Defense

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PHRD5935 Pharm/Tox Lecture 10 - Mechanisms of Toxicity and Cellular Defense
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2014-05-19 05:45:55
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Mechanisms Toxicity Cellular Defense
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Mechanisms of Toxicity and Cellular Defense
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  1. 4 toxic responses to drugs
    • 1) altered physiology
    • 2) covalent mod of cellular constituents
    • 3) free radicals
    • 4) disturbances of cellular homeostatic mechs
  2. agents that are electron deficient (nonionic or cationic-positive charge) 

    (eg: ketones, epoxides, a,b-unsaturated ketones/aldehydes, quinones, quinoneimines)
    electrophiles
  3. when are electrophiles produced?
    during drug oxidations
  4. toxicological importance of electrophiles
    they permanently alter endogenous molecules
  5. toxic effects of electrophiles on DNA
    react w/ nucleophilic sites in DNA (O6 or N7 in guanine) and/or phosphate backbone
  6. toxic effects of electrophiles on proteins
    react w/ nucleophilic sites in proteins (eg: -SH, -NH2) leading to inactivation of proteins
  7. main metabolizing enzyme of APAP
    CYP2E1
  8. reaction of NAPQI (APAP reactive metabolite) w/ GSH yields what excretable molecule?
    mercapturic acid
  9. a compound with an unpaired electron
    free radical
  10. how are free radicals produced?
    • by enzymes which catalize 1e- redox rxns
    • photolysis or radiation (homolytic cleavage of a covalent bond)
  11. 3 toxic consequences of free radicals
    • 1) interaction w/ DNA
    • 2) oxidative damage
    • 3) lipid peroxidation
  12. the most active free radical
    hydroxy radical (.OH)
  13. how are hydroxy free radicals created?
    metals react w/ H2O2
  14. 2 drugs that cause toxic effects by interaction w/ DNA
    • adriamycin
    • bleomycin
  15. 2 ways redox cycling damages DNA
    • 1) hydroxy radicals react w/ backbone, resulting in DNA breaks
    • 2) ROS cause oxidative damage
  16. chain rxn of free radicals w/ lipids (PUFA & cholesterol)
    lipid peroxidation
  17. consequences of lipid peroxidation
    • destroys cell membranes & leads to fcnal impairment of membrane bound proteins (eg: G6P-ase)
    • generates aldehydes
  18. 3 key destructive aldehydes generated during lipid peroxidation
    • 1) malondialdehyde
    • 2) 4-hydroxynonenal
    • 3) acrolein
  19. 3 types of agents that cause disturbance of cellular homeostatic mechanisms
    • 1) agents that disturb ionic balances
    • 2) agents that disturb energy production
    • 3) agents that disturb redox balance
  20. protection against drug metabolite reactive species (2)
    • 1) polar metabolite generation
    • 2) enzymes (ALDH, NQO1)
  21. protection against free radical reactive species (4)
    • 1) enzymatic antioxidants
    • 2) non-enzymatic antioxidants
    • 3) metal sequestering agents
    • 4) DNA-repair
  22. 3 ways to generate polar metabolites
    • 1) sulfation via sulfotransferases
    • 2) glucuronidation via UDP-glucuronyltransferase (UGT)
    • 3) rxn w/ glutathione via glutathione-S-transferase (GST)
  23. concentration of GSH in erythrocytes? hepatocytes?
    • erythrocytes: 2mM
    • hepatocytes: >5mM
  24. tripeptide that plays a central role in cellular defense
    glutathione (GSH)
  25. 2 chemical rxns w/ GSH
    • 1) direct conjugation by addition
    • 2) direct conjugation by displacement
  26. how glutathione conjugates are excreted (2)
    • 1) unchanged in bile
    • 2) metabolism to mercapturic acid & excreted in urine (eg: naphthalene)
  27. enzyme that bypasses redox cycling & formation of radicals from menadione
    NQO1 (NADPH-quinone oxidoreductase)
  28. enzymatic antioxidant systems that provide protective mechanisms against free radicals
    • i) SOD, CAT, GPO
    • ii) GSH peroxidase/GSSG reductase
  29. non-enzymatic antioxidants that provide protective mechanisms against free radicals (2)
    • 1) vit E
    • 2) vit C
  30. enzyme that forms H2O2 from superoxide anion (O2.-)
    SOD (superoxide dismutase)
  31. enzymes that form water from H2O2
    • GPO (glutathione peroxidase)
    • CAT (catalase)
  32. conversion of GSSG to GSH only occurs in the presence of what cofactor and enzyme?
    • NADPH
    • GSSG reductase
  33. 4 NADPH regenerating systems
    • 1) G6PDH (**imp in erythrocytes**)
    • 2) isocitrate dehydrogenase
    • 3) 6-phosphogluconate dehydrogenase
    • 4) mallic enzyme
  34. lipid soluble compound that protects against lipid peroxidation
    vitamin E
  35. water soluble radical scavenger
    vitamin C
  36. 4 other important antioxidants
    • 1) bilirubin/biliverdin
    • 2) beta-carotene
    • 3) uric acid
    • 4) glutathione
  37. characteristics of ideal chelating agents
    • ***have low affinity for essential metals (Ca, Zn)
    • water soluble
    • resistant to metabolism
    • able to reach site of metal storage
    • capable of forming non-toxic complexes w/ metals
  38. notable drugs that are chelators of Ca & Mg ions
    tetracycline abx
  39. enzyme that "commits suicide" to remove/repair DNA mutations
    O6methylguanine - DNA methyltransferase

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