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Biotransformation

Results of Biotransformation. Parent molecule becomes more polarMolecular weight and size incresedExcretion is facilitatedMetabolic consequencesHalf life is decreasedDuration of exposure reducedAccumulation in body reduced. General points about biotransformation . Enzymes involved are less sp

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Biotransformation

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    1. Biotransformation

    2. Results of Biotransformation Parent molecule becomes more polar Molecular weight and size incresed Excretion is facilitated Metabolic consequences Half life is decreased Duration of exposure reduced Accumulation in body reduced

    3. General points about biotransformation Enzymes involved are less specific Foreign compounds can enter endogenous pathways Foreign compounds can undergo more than one metabolic transformation Metabolism involves sequential steps(not always phase 1 then phase 2) Rates of various reactions can vary Biotransformation doesn’t necessarily lead to detoxication

    4. Biotransformation Metabolic conversion of endogenous and xenobiotic nonpolar compounds to more polar or water-soluble compounds 2 groups of reactions: Phase I Hydrolysis reactions Reduction reactions Oxidation reactions Phase II Conjugation reactions

    5. Enzyme Systems 2 major metabolizing systems Cytochrome P450 monooxygenase system (Phase I) Oxidation and some reduction reactions Conjugation or synthetic system Phase II Other enzymes Esterases Dehydrogenases Hydrolases Reductases

    6. Distribution of Enzymes Liver primary source Microsomes Endoplasmic reticulum Cytosolic Kidney Lung GI tract Eye

    7. Phase I Reactions Oxidative Reactions Microsomal Cytochrome P450 catalyzed reactions Flavin containing monooxygenase (FMO) Nonmicrosomal Alcohol and aldehyde dehydrogenases Monoamine and diamine oxidases Deamination Cooxidation Prostaglandin synthesis Hydrolysis Esterases

    8. Phase I Reactions Reduction Reactions Microsomal Cytochrome P450 catalyzed reactions Nonmicrosomal Glutathione reductases Disulfide reduction Ketone and aldehyde reductions Epoxide hydration

    9. Cytochrome P450 Monooxygenase System Located in the endoplasmic reticulum Primarily smooth ER Detoxifies/activates the highest number of xenobiotics Monooxygenation One atom of a molecule of oxygen is incorporated into the substrate Other atom reduced to water RH + O2 + NADPH +H+ ? NADP+ + ROH + H2O

    10. Cytochrome P450 Heme protein Many isoforms of the P450 enzymes Coupled enzyme system NADPH cytochrome P450 reductase NADH cytochrome b5 reductase NADPH is the hydrogen donor

    11. CP450 Catalytic Cycle Binding of substrate to oxidized P450 One electron reduction of CP450 by NADPH CP450 reductase Formation of ternary oxygenated complex One electron reduction by cytochrome B5 reductase Loss of one molecule of oxygen as water and transfer of one molecule of water to the substrate Release of oxidized substrate Return of CP450 to oxidized state

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