1. Transportation and Transformation of Xenobiotics
Chapter 3
Transportation and Transformation of Xenobiotics
Toxicology - Chaper 3
卫生毒理学

2. Section 1
Absorption
Toxicology - Chaper 3

3. Cell Membranes
A phopholipid bilayer with polar head groups on both surfaces.
Proteins or glycoproteins are inserted in or across the bilayer.
The fluid character of membranes is determined largely by the structure and relative abundance of unsaturated fatty acids.
Toxicology - Chaper 3
卫生毒理学

4. Transport Passive transport: simple diffusion; filtration
Special transport: active transport; facilitated diffusion; additional transport processes: phagocytosis and pinocytosis
Toxicology - Chaper 3
卫生毒理学

5. Absorption
Absorption: Transfer of a chemical from the site of exposure into the systemic circulation by cross body membranes.
The main sites of absorption are the GI tract, lung and skin, but there are other ways of administration including enteral and parenteral routes.
Toxicology - Chaper 3
卫生毒理学

6. Factors altering the GI absorption of toxicants
pH of the GI
Residency time of compounds
Physical properties of chemicals
First-pass effect
Food: ion, milk
Toxicology - Chaper 3
卫生毒理学

7. Factors altering the lung absorption of toxicants
Gases and vapors
Blood-to-gas partition-coefficient
Aerosols and particles
Solubility
Size: 2-5μmainly deposited in the tracheobronchium
Toxicology - Chaper 3
卫生毒理学

8. Factors altering the skin absorption of toxicants
Molecular weight
Lipid/water solubility
Condition of the skin
Cutaneous blood flow
Solvents
Toxicology - Chaper 3
卫生毒理学

9. Distribution and Excretion
Section 2
Distribution and Excretion
Toxicology - Chaper 3

10. Distribution Plasma water Extracellular water Intracellular water
Tissue binding
Redistribution: organ affinity
Toxicology - Chaper 3
卫生毒理学

11. Storage of toxicant in tissues
Plasma protein
Liver and kidney
Fat
Bone
Barrier: blood-brain, placenta
Toxicology - Chaper 3
卫生毒理学

12. Excretion Urinary excretion Fecal excretion Biliary excretion
Intestinal excretion
Exhalation
Milk
Sweat and saliva
Toxicology - Chaper 3
卫生毒理学

13. Principles of biotransformation of xenobiotics
Section 3
Principles of biotransformation of xenobiotics
Toxicology - Chaper 3

14. Definition
Conversion of lipophilic xenobiotics to water-soluble chemicals by a process catalyzed by enzymes in the liver and other tissues.
In most cases, biotransformation lessens the toxicity of xenobiotics, but many must undergo the process to exert their toxic effects.
Toxicology - Chaper 3
卫生毒理学

15. General principles
Broad specificity of xenobiotic biotransforming enzymes such as P450 enzymes.
Biotrasformation versus metabolism
Sterrochemical difference of biotransformation may lead to different metabolites
Phase I and Phase II biotransformation
Toxicology - Chaper 3
卫生毒理学

16. Phase I and phase II biotransformation
Section 4
Phase I and phase II biotransformation
Toxicology - Chaper 3

17. Phase I biotransformation
Hydrolysis: functional group such as carboxylic acid ester, amide, thioester, acid anhydride
Reduction: azo- and nitro-, carbonyl, disulfide, sulfoxide, quinone, dihydropyrimidine
Oxidation: alcohol, aldehyde, ketone, monoamine, aromatization, molybdenum, flavin Key oxidation enzyme: cytochrome P450
Toxicology - Chaper 3
卫生毒理学

18. Cytochrome P450
Activation of xenobiotics by P450 leads in most cases to detoxication, but some toxicities like tumorigenicity of a chemical depends on its activation.
Some P450 enzymes in human liver microsomes are inducible which usually lowers blood level of the xenobiotics.
Inhibition of P450 falls into 3 categories: the competition between 2 chemicals metabolized by the same P450; by different P450; and by suicide inactivation.
Toxicology - Chaper 3
卫生毒理学

19. Phase II biotransformation
Reactions: glucuronidation, sulfonation, acetylation, methylation
Conjugation with glutathione and amino acid can result in a large increase in xenobiotic hydrophilicity to greatly promote the excretion of foreign chemicals
Most phase II biotransforming enzymes are mainly located in the cytosol, and the reactions are much faster than phase I reactions
Toxicology - Chaper 3
卫生毒理学

20. The dog that did not bark
Xenobiotics are never phosphrylated which would require less ATP and would be directly converted to water-soluble conjugates.
Three reasons for the dog:
High intracellular levels of phosphrilated chemicals may jeopardize cell viability
Phosphorylation is a mechanism for trapping endogenous substrates
Phosphrylation plays important role in cell signaling
Toxicology - Chaper 3
卫生毒理学

21. Section 5
Toxicokinetics
Toxicology - Chaper 3

22. Toxicokinetics
Definition: the modeling and mathematical description of the time course of disposition of xenobiotics in the whole organism.
Classic toxicokinetics
One-compartment model
Two-compartment model
Model parameters: elimination, apparent volume of distribution, clearance, bioavailability
Toxicology - Chaper 3
卫生毒理学

23. Toxicokinetics Physiologic toxicokinetics
Basic model structure: blood, brain, kidney, liver, intestine, total body
Compartment: perfusion-limited, diffusion-limited, specialized
Model parameters: anatomic, physiologic, thermodynamic, transport
Toxicology - Chaper 3
卫生毒理学

24. Transportation and transformation are linked together to function
Toxicology - Chaper 3
卫生毒理学