PHRD5915 Drug Design Lecture 3 - Phase I Metabolism

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daynuhmay
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266367
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PHRD5915 Drug Design Lecture 3 - Phase I Metabolism
Updated:
2014-03-14 02:10:31
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Phase Metabolism
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Phase I Metabolism
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  1. what must be present for a reductive reaction to occur in a P450 catalyzed reaction?
    halogen (eg: halothane)
  2. What type of reaction is this:

    SH + O2 + NADPH + H+  SOH + H2O+NADP+
    oxidative reaction
  3. terminal oxidase of the MFO (mixed-function oxidase) electron-transfer system
    CYP
  4. what CYP uses as a source of reducing equivalents
    NADPH
  5. type of protein CYP is
    heme
  6. axial ligand typical of CYP450, CPO, and NOS enzymes
    iron (III) protoporphyrin IX with a cysteinate
  7. active oxygen species of CYP450, CPO, and NOS enzymes
    oxoiron(IV) porphyrin cation radical 

    (often called Compound I)
  8. why is cysteine preferred over histidine in heme enzymes?
    cysteine is a better electron donor
  9. what allows CYP450 to accommodate diverse substrates?
    large presence of numerous -helices (more translational motion than -sheets)
  10. Type I spectrum: max & min wavelengths
    • max: 390nm
    • min: 420nm
  11. substrate (S) binds to active site of E close to the heme group, displacing H2O from distal axial position of heme iron
    Type I
  12. Type II spectrum: max & min wavelengths
    • max: 440nm
    • min: 410nm
  13. substrate (S) binds directly to the heme iron
    Type II
  14. - induced by change in electronic state of active site
    - reduces ferric heme to ferrous heme
    transfer of first e- from NAD(P)H via CYP450 reductase
  15. where 2nd e- transferred in P450 cycle is from (2)
    • P450 reductase
    • cytochrome b5
  16. result of transfer of e- via the electron-transport system
    reduction of dioxygen adduct to negatively charge peroxo group (loss of 1 of 2 O's)
  17. how P450 Compound 1 is formed
    • (Step 5 of cycle)
    • peroxo group is protonated twice by water or surrounding amino-acid side chains, releasing 1 H2O & forming a reactive species (P450 Compound 1)
  18. what happens to bond length during transition from ferric superoxide (O2-) to ferric peroxide (O22-) P450
    increased bond length (1.33 -> 1.49 Angstroms)
  19. main evolutionary goal of biotransformation
    increase the rate of excretion of xenobiotics or drugs
  20. 5 characteristics of Phase I products (result of drug metabolism)
    • 1) inactivation (eg: oxidation of EtOH)
    • 2) conversion of active drug to another active one (codeine/heroin -> morphine)
    • 3) conversion of drug to toxic metabolites (APAP)
    • 4) activation of prodrug
    • 5) product might undergo phase II
  21. characteristics of a prodrug (3)
    • 1) pharmacologically inactive
    • 2) converted rapidly to active metabolite (usually hydrolysis of ester or amide bond)
    • 3) maximizes the amount of active species that reaches site of action
  22. what is formed every time a demethylation rxn occurs
    formaldehyde

  23. what is formed every time a deethylation rxn occurs
    acetaldehyde

  24. all epoxides are very (electrophilic/nucleophilic)
    electrophilic
  25. enzyme that opens up epoxide in styrene oxide
    epoxide hydrolase (EH)
  26. product of reductive dehalogenation reactions
    free radicals
  27. dealkylation
  28. reductive/oxidative dehalogenation
  29. dehydrogenation
  30. epoxidation of a double bond
  31. hydroxylation
  32. heteroatom oxygenation
  33. oxidation/reduction
  34. 4 non-CYP drug metabolizing enzymes
    • 1) monoamine oxidase (MAO)
    • 2) alcohol & aldehyde dehydrogenase
    • 3) xanthine oxidase
    • 4) flavin monooxygenases (FMOs)
  35. where is CYP450 located?
    in the smooth ER of all major organs & tissues

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