Mixed function oxidase System (cytochrome 450 System)--Phase I Reactions

• Microsomes have been used to study mixed function oxidases

  • Mixed function oxidases are enzymes that metabolize drugs (and other chemicals)

  • 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

• Cytochrome P450 Enzyme Induction:

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

    • Increasing enzyme synthesis rate (induction) and/or

    • Decreasing enzyme degradation rate (the rate at which the enzyme is degraded to inactive forms by the cell).

• 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)) are metabolized by a cytochrome P450:

    • The antibiotic metabolites complex with cytochrome heme-iron which results in a complex that is catalytically inactive.

  •  Chloramphenicol (Chloromycetin) is metabolized by cytochrome P450 to a reactive, alkylating metabolite that itself inactivates cytochrome P450.

  •  Other inactivators:

    • Mechanism of Action: Some drugs target the heme (Iron) component and inactivate.

    • Steroids:

      • Ethinyl estradiol (Estinyl)

      • Norethindrone (Aygestin)

      • Spironolactone (Aldactone)

    • Others:

      • Propylthiouracil

      • Ethchlorvynol (Placidyl)