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

Section 1 Absorption Toxicology - Chaper 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Section 5 Toxicokinetics Toxicology - Chaper 3

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

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

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