How Chemicals Move Into, Around & Out of the Body ENV

Transcription

1 How Chemicals Move Into, Around & Out of the Body 1

2 ADME The movement of toxicants into, around and out of the body is commonly referred to as ADME! Absorption! Distribution! Metabolism! Elimination 2

3 Cell & Tissue Barriers to Toxicants Absorption Distribution Excretion Toxicants must cross cellular and Assue barriers 3

4 SelecAve Permeability of Cell Membranes Bilaminar lipid cell membrane forms lipophilic barrier that limits movement of water soluble molecules Ion channels form pores for selecave diffusion of small hydrophilic molecules SelecAve carrier proteins transport molecules 4

5 Major Cell Membrane Transport Processes Simple passive diffusion Facilitated passive diffusion AcAve membrane transport 5

6 Simple Passive Diffusion Chemical moves down concentraaon gradient Does not require cell energy Does not require transport proteins 6

7 Toxicant Chemical ProperAes that Promote Passive Diffusion Lipophilicity of a toxicant promotes its diffusion across the lipid bilayer of cell membranes Lipophilicity is quanafied by the paraaon constant/ coefficient (Kow) Small (< MW) hydrophilic molecules may diffuse through membrane ion channels Channels are regulated Open channels allow diffusion of toxicants that meet channel selecavity characterisacs Usually applies to small ionic toxicants Large hydrophilic molecules will not diffuse across cell membranes 7

8 IonizaAon is Important IonizaAon is defined by the presence of molecular charge Chemical acids and bases are molecules that can become ionized depending on ph of soluaon IonizaAon decreases lipid solubility IonizaAon increases water solubility because water molecules are polar 8 alevelnotes.com

9 Fick s Law Describes Simple Passive Diffusion Fick s Law: Rate of simple passive diffusion = K(A)(C2-C1) where A = surface area at site of absorpaon C2 C1 = concentraaon difference across the membrane K = constant 9

10 Simple Passive Diffusion Changes in toxicant concentraaon gradient affects rate of absorpaon by simple passive diffusion ConcentraAon gradients across cell membranes can change due to IonizaAon on one side of membrane only Binding to a molecule in abundance on one side of membrane only Metabolism in one compartment and not the other 10

11 Refresh Your Learning According to Fick s Law, what are the two main factors that determine the rate of passive diffusion across a membrane? 11

12 Facilitated Passive Diffusion Mediated by membrane carrier proteins Moves toxicants down a concentraaon gradient SelecAve (only certain chemicals) Saturable (no increased transport above criacal concentraaon) Increases absorpaon of chemicals when present in low concentraaons Can transport ionized toxicants with low lipid solubility 12

13 AcAve Membrane Transport Requires cell energy to move molecules across cell membrane Can transport toxicants against concentraaon gradient Can transport toxicants with low lipid solubility or that are ionized Can concentrate toxicants in Assue 13

14 Major AcAve Transport Mechanisms Membrane carrier protein SelecAve Saturable Endocytosis Phagocytosis (paraculates) Pinocytosis (liquid) 14

15 Wrapping Up Membranes What is the major characterisac of acave transport that disanguishes it from passive transport? A. AcAve transport requires cell energy B. AcAve transport is selecave C. AcAve transport is saturable 15

16 Absorp1on into the Body! Absorption! Distribution! Metabolism! Elimination 16

17 Entry Into the Organism Major routes skin lungs gastrointesanal (GI) tract Minor routes wounds injecaon 17

18 Transport Across Epithelia Epithelial Assues form the barriers between the inside and outside of the body & body compartments Intercellular pores of epithelia limit diffusion between cells based on MW Degree of occlusion varies with Assue However, most toxicant transport is across lipid cell membrane 18

19 Simple Passive Diffusion Across Epithelium Simple passive diffusion across epithelial Assue is predicted by the modified Fick s Law: Rate of simple passive diffusion = K(A/D)(C2-C1) where A = surface area at site of absorpaon C2 C1 = concentraaon difference across the membrane K = constant D = thickness at site of absorp5on 19

20 Factors that Affect ConcentraAon Gradient & Therefore AbsorpAon Blood flow removes the toxicant away from the site of absorpaon à maintains the concentraaon gradient & favors absorpaon Anything that changes the chemistry of a toxicant once absorbed à maintains the concentraaon gradient & favors absorpaon Binding of toxicant to proteins & lipids in blood Metabolism of toxicant IonizaAon of toxicant due to ph differences 20

21 Skin (Dermal) Because it is the body covering, the skin is the first line of defense The outermost layer (stratum corneum) is the most important barrier to toxicant entry Due to the protein keraan 21

22 Biological Factors AffecAng Skin AbsorpAon Degree of cornificaaon (due to keraan) based on locaaon on body CondiAon of skin cracks, burns, wounds, punctures, abrasions Species differences 22

23 GastrointesAnal Tract (Oral) AbsorpAon varies along the gastrointesanal (GI) tract Mouth & esophagus have minor absorpaon roles for toxicants due to limited Ame of contact Stomach Takes ~2 hours to pass through 23

24 Small IntesAne Major site of absorpaon Very large surface area (~200 m 2 ) surface is folded 4-5 million villi project into lumen each villus has ~2,500 microvilli Capillary beds within villi allow for high absorpaon into blood from small intesane 24

25 Small IntesAne Most toxicants are absorbed by passive diffusion Pinocytosis More acave in newborns Passive & acave carrier-mediated transport can be important for certain toxicants Lead (transported by calcium & iron transporters) More acave in newborns & younger animals 25

26 Small IntesAne Portal vein carries blood from GI tract to liver before distribuaon throughout body First pass effect IntesAnal bacteria metabolize some toxicants Toxicants can become more or less toxic Toxicants can become more lipophilic to increase absorpaon from large intesane 26

27 Benzoic Acid This is an example to illustrate how ph affects toxicant solubility the principles are important, not the details of the example COOH COO --- ph % Nonionized Stomach Intestine H + % ionized Blood 27

28 Large IntesAne Major site of water absorpaon Concentrates toxicants as feces are formed 28

29 AnAdote to Ingested Poisons Carbon / acavated charcoal Binds variety of molecules Poorly absorbed Excreted in feces 29

30 Quick Review Name & explain four factors that favor absorpaon of toxicants in the small intesane 30

31 Respiratory Tract Main funcaon is oxygenaaon of blood Gas exchange of oxygen & carbon dioxide occurs in alveoli Lung epithelium of alveoli is a single, thin cell layer Facilitates gas exchange Easily damaged V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis,

32 Respiratory Tract AbsorpAon of Gases Aerosols ParAculates Toxicants absorbed from lungs are returned to heart and directly circulated throughout body (without first passing through the liver) V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis,

33 Respiratory Tract Defenses Hairs of nose trap large paracles & aerosols Fluid covering of nose & pharynx absorbs watersoluble & reacave gases, aerosols & paraculates Increasingly restricted diameter of respiratory tract limits penetraaon of paraculates and aerosols Mucous covering of respiratory tract (except for alveoli) traps substances Cilia of trachea & bronchi move mucous toward pharynx (swallowed) mucociliary escalator 33

34 Toxicant AbsorpAon From Lungs Most gases are nonionized & absorbed into blood by simple diffusion ParAculates are phagocytosed by alveolar macrophages 34

35 Physiologic Modifiers of Lung AbsorpAon RespiraAon rate RespiraAon rate determines exchange of air in alveoli Increased respiraaon rate increases absorpaon of inhaled toxicants Heart rate Heart rate determines rate of delivery of bloodborne toxicants to and from lungs Increased blood circulaaon increases absorpaon of toxicants, especially toxicants with high solubility in blood 35

36 Important Concepts Different mechanisms by which toxicants move across cell membranes & their disanguishing characterisacs How toxicant chemistry is important to membrane absorpaon Important biological & chemical characterisacs that impact absorpaon through dermal, oral & inhalaaon routes of exposure 36