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Oncology General Principles Continued

 

Mixed function oxidase System (Cytochrome 450 System)--Phase I Reactions44 
  • Microsomes have been used to study mixed function oxidases

    • Drug metabolizing enzymes are located in lipophilic, hepatic endoplasmic reticulum membranes.  Smooth endoplasmic reticulum contains those enzymes responsible for drug metabolism.

  • The reaction:

    • one molecule oxygen is consumed per substrate molecule

    • one oxygen atom -- appears in the product; the other in the form of water

    • Oxidation-Reduction Process:

Cytochrome p450 cycle (diagram by  Matthew Segall, 1997)

  1. "The binding of a substrate to a P450 causes a lowering of the redox potential by approximately 100mV, which makes the transfer of an electron favourable from its redox partner, NADH or NADPH.

  2. The first reduction -The next stage in the cycle is the reduction of the Fe3+ ion by an electron transfered from NAD(P)H via an electron transfer chain.

  3. Oxygen binding An O2 molecule binds rapidly to the ion Fe2+ forming Fe2+-O2

  4. Second reduction A second reduction is required by the stoichiometry of the reaction. This has been determined to be the rate-determining step of the reaction

  5. O2 cleavage: The O2 reacts with two protons from the surrounding solvent, breaking the O-O bond, forming water and leaving an Fe-O3+ complex.

  6. Product formation The Fe-ligated O atom is transferred to the substrate forming an hydroxylated form of the substrate.

  7. Product release The product is released from the active site of the enzyme which returns to its initial state."--Matthew Segall, 1997

  • "The active site of substrate-free cytochrome p450: Note the water molecule (which can be seen as a single oxygen atom) that forms the sixth axial ligand of the haem iron. Oxygen atoms are shown in red, nitrogen in light blue, sulphur in yellow and iron in dark blue. Carbon atoms are shown in grey as bonds only and hydrogens have been omitted from this figure for clarity."

  • "The active site of camphor-bound cytochrome p450cam , an example of a substrate-bound system. Note the absence of the water molecule which formed the sixth axial ligand of the haem iron in the substrate-free enzyme."

  • " A representation of with bound camphor. The enlarged active site region shows the camphor substrate, haem moiety and cysteine residue which forms the distal haem ligand. In the representation of the full enzyme the protein backbone is shown in green, the haem moiety in blue and the substrate is coloured according to atomic species. Oxygen atoms are shown in red, carbon in grey, nitrogen in light blue, sulphur in yellow and iron in dark blue."-diagrams and text  by  Matthew Segall, 1997

  • Cytochrome P450 Enzyme Induction:

    • Following repeated administration, some drugs increase the amount of P450 enzyme usually by:

      • increase enzyme synthesis rate (induction)

      • reduced enzyme degradation rate

  • Cytochrome P450 enzyme inhibition:

    • Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

      •  Cimetidine (Tagamet) (anti-ulcer --H2 receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

        • testosterone

        • other coadministered drugs

        • Mechanism of Action: competitive inhibition

    •  Catalytic inactivation of cytochrome P450.

      •  Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

        • metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

      •  Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

      •  Other inactivators: Mechanism of Action: -- targeting the heme moiety:

        • steroids:

          • ethinyl estradiol (Estinyl)

          • norethindrone (Aygestin)

          • spironolactone (Aldactone)

        • others:

          • propylthiouracil

          • ethchlorvynol (Placidyl)

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