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Effect is the outcome of interaction between susceptibility and exposure

Effect is the outcome of interaction between susceptibility and exposure. What makes a particular organ or species susceptible ?. An example of metabolic activation-detoxication. Organophosphate Insecticides: Parathion Malathion. Parathion. Malathion. Hydrolysis enzymes.

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Effect is the outcome of interaction between susceptibility and exposure

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  1. Effect is the outcome ofinteraction between susceptibility and exposure

  2. What makes a particular organ or species susceptible ?

  3. An example of metabolic activation-detoxication • Organophosphate Insecticides: • Parathion • Malathion

  4. Parathion

  5. Malathion

  6. Hydrolysis enzymes • Serum cholinesterase BChE • Serum paraoxonase PON1 • Polymorphisms in PON1 – differential sensitivity

  7. Exposure • External exposure – ambient air, water • Dose received by body • Dose at target organ • Dose at target tissue • Dose at target molecule • Molecular dose • Repair

  8. Exposure – DoseHow are they related ?Can we measure them ?How can we describe the crucial steps so that we can estimate what we can’t measure?

  9. Enzymes: Biological catalysts • Proteins • May have metals at active site • Act on “substrate” • May use/require co-factors

  10. Kinetics of Enzyme-catalyzed Reactions Michaelis-Menten Equation: v = Vmax * [S] Km + [S] First-order where Km >> [S] Zero-order where [S] >> Km

  11. First-Order Processes • Follow exponential time course • Rate is concentration-dependent v = [A]/t = k[A] • Units of k are 1/time, e.g. h-1 • Unsaturated carrier-mediated processes • Unsaturated enzyme-mediated processes

  12. Second-Order Processes • Follow exponential time course • Rate is dependent on concentration of two reactants v = [A]/t = k[A]*[B]

  13. Steady-state kinetics k1 k2 E + S ES E + P [ES] is constant, i.e. ES/t = 0 k-1

  14. Saturated metabolism • Saturated activation • Saturated detoxication

  15. Uptake Higher concentration Carrier Pore Diffusion Lipid bilayer Facilitated diffusion Active transport Filtration Lower concentration

  16. Absorption - uptake • Passive diffusion • Filtration • Carrier-mediated Elimination - excretion

  17. kin kout The single compartment(one compartment) model

  18. Kinetics of absorption • Absorption is generally a first-order process • Absorption constant = ka • Concentration inside the compartment = C • C/t = ka * D where D = external dose

  19. Kinetics of elimination • Elimination is also generally a first-order process • Removal rate constant k, the sum of all removal processes • C/t = -kC where C = concentration inside compartment • C = C0e-kt • Log10C = Log10C0 - kt/2.303

  20. First-order elimination Half-life, t1/2 Units: time t1/2 = 0.693/k

  21. First-order decay of plasma concentration

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