Toxicology Exam 1 Flashcards

Question

Interactions between xenobiotics: Synergy

Answer 1

Two poisons together produce maximal response that is greater than the sum of individual responses

Answer 2

One poison has no response by itself but enhances the response of another poison

Answer 3

Functional Antagonism: Response of two xenobiotic counterbalance each other Dispositional Antagonism: One xenobiotic affects absorption, distribution, or elimination of another Chemical Antagonism: Response of one xenobiotic is neutralized by another through direct chemical interactions

Answer 4

The term disposition is from the verb 'to dispose' or to get rid of. In pharmacology, disposition refers to what happens to the drug after it enters the body, including distribution, and elimination processes.

Answer 5

Xenophobic → Absorption → Distribution → Elimination (ADME) Absorption Distribution Metabolism (biometabolism or biotransformation) Elimination

Answer 6

ADME determines level of xenobiotic at site of action Major determinant of toxic potential of poisons

Answer 7

Dose Chemistry of the xenobiotic itself (e.g., hydrophobicity) Rate of absorption Sequestration in non-target tissue (fat tissue, adipose, blood) Biotransformation to active/inactive metabolite Rate of elimination

Answer 8

Quantitative modeling of xenobiotic disposition

Answer 9

1) Gastrointestinal tract (alimentary system) - Digestion (breakdown of food) - Absorption of nutrients - Water absorption - Xenobiotics include chemicals (e.g., weak acids/bases, organic) or particulates 2) Lungs (pulmonary system) - Oxygen absorption - Xenobiotics include gas, vapors of volatile liquids, aerosols, and particulates 3) Skin (dermis) - Maintain body temperature - Prevent dehydration - Xenobiotics include oils, organic chemicals, venoms

Answer 10

1) GI tract - Removal of digestion waste products (feces) 2) Liver (hepatic system) - Dietary nutrient storage and processing - Bile production (aids in lipid digestion in the GI tract) 3) Lungs - C02 elimination 4) Kidneys (renal system) - Urine production and metabolic waste removal - Maintenance of blood volume, salt content, pH Lymphatic system Lymph - Drainage of fluid with waste from organs - Returns wastes to blood for elimination via liver/kidneys - Immune system (lymph nodes)

Answer 11

Heart Blood vessels - Arteries: carry oxygenated blood to tissues - Veins: carry deoxygenated blood away from tissues - Capillaries: nutrient/waste exchange in tissues Blood - Composed of fluid, protein, and cells - Distribution of nutrients to tissues (e.g., O2, glucose) - Removal of metabolic waste from tissues (e.g., CO2, lactate)

Answer 12

Barrier property of cell (plasma) membranes Cell membranes are lipid bilayers composed of glycerol phospholipids Cell membranes are semipermeable selectivity barriers Hydrophobic (does not like water) fatty acid groups efficiently repel hydrophilic molecules Hydrophilic/polar (likes water) head group can antagonize hydrophobic molecule penetration to some extent

Answer 13

1) Passive transport Simple diffusion Filtration (between the cell) 2) Specialized transport - charge molecules Facilitated diffusion Active transport

Answer 14

Paracellular diffusion (between the cell) Transcellular diffusion (through the cell) Two driving forces work together: Brownian motion and Concentration gradient

Answer 15

Lipophilicity vs. polarity (hydrophobicity) - measured by LogP - low lipophilicity is low log p Charge (hydrophilicity) - measured by pKa Values provide some predictive information regarding type of transportation (paracellular vs. transcellular)

Answer 16

Occurs in capillary beds of circulatory system Depends on endothelial cell type/connections Three types of endothelial cells that line capillary vessels Continuous: tight junctions (Ex skin, lung, GI, brain) Discontinuous: no tight junctions (Ex many capillaries) Fenestrated: holes (Ex kidneys, liver) Two driving forces 1) Blood pressure: determined by the heart 2) Osmotic pressure: determined by albumin in blood Filtration is determined by water flowing out of the tissue

Answer 17

Driving force is concentration gradient Requires Solute Carrier (SLC) proteins Characteristics of SLCs - Reversible - Involved in influx/absorption - Involved in efflux/excretion - Transport endogenous or xenobiotic molecules - Molecules transported can be anionic, cationic, or organic in nature SLCs are a large family of transporter proteins that are classified by substrate transported

Answer 18

Transport against a concentration gradient Driving force is cellular ATP Types of active transport channels - Sodium-potassium ATPase - Sodium-calcium exchanger - Calcium pumps - ABC transporters Are plasma membrane proteins Split up into Gut, Liver, Kidneys, Brain, Placenta, Testis ABC transporters hydrozole ATP to get energy

Answer 19

- Primarily transports xenobiotics out of cells/tissues/body (efflux/excretion) - Endothelial cells “pump” xenobiotics back into blood - Target cells pump xenobiotics back into interstitial fluid - Performs a protective role by preventing xenobiotic from reaching its target - Mice lacking MDR/P-gp had 50-fold increase in accumulation of a substrate xenobiotic in brain - The LD50 for a substrate xenobiotic was also decreased >70-fold in mice lacking MDR/P-gp

Answer 20

Gastrointestinal tract (GI) or Alimentary Tract: - Continuous muscular tube - Lined by specialized epithelial cell layer connected by tight junctions - The lumen (inside the tube) is exterior to the body - Contains commensal/mutualistic microbial flora (microbiome) Accessory digestive organs: -Liver/gallbladder: bile - Pancreas: digestive enzyme/bicarbonate Subdivision of the GI tract: - Mouth (intake)/tongue - Pharynx/esophagus - Stomach - Small intestine - Large intestine (cecum) - Colon - Rectum and anus (output)

Answer 21

- Gastric (stomach) and enteric (intestinal) mucosa - pH of GI lumen (e.g., ionization state) - Transit time - GI contents - Surface area of tubes - Blood flow (law of mass action) - Microbial biometabolism - Bile acids (lipophilic surfactant produced by liver)

Answer 22

Gastric mucosal layer: epithelial cell layer of stomach - Specialized in acid production - Food stimulates gastrin (hormone) released into the circulation - Gastrin stimulates secretion of H+ by gastric mucosa cells - Combines with Cl- in the stomach lumen to form hydrochloric acid (HCl) - Very low pH (pH between 1 and 2) Small surface area - Mucosa layer is relative smooth compared to the small intestines *weak acids is favorable in stomach bc of pka and ph - stomach breaks down proteins which are charged

Answer 23

Pancreas - Pancreas is an accessory organ of GI - Produces bicarbonate buffer and digestive enzymes - Secretes >1 liter of juice per day into the duodenum of the small intestines (first section after stomach) - Higher pH above 6 Large surface area - Enteric mucosal layer are epithelial cells lining the GI - These cells are specialized in absorption - Villi structure of wall and microvilli of enterocytes * Increased 600-fold over stomach *weak bases are more absorbed in small intestine

Answer 24

Absorption of weak acids is more favorable in stomach However, absorption of weak acids can occur in the small intestines due to large surface area and the action of transporter proteins Absorption of weak bases is most favorable in intestines

Answer 25

Upper respiratory tract: nose/mouth, nasal passage, pharynx, trachea Lower respiratory tract: Lungs - Bronchi/bronchioles (airways) - Alveoli (air sacs)

Answer 26

Gases: carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone, radon Vapors: volatile liquids such as formaldehyde, chloroform, and certain anesthetics Aerosols/particles: water droplets, coal dust, asbestos, smoke

Answer 27

Gas/vapor absorption involves partitioning between two phases, atmosphere (gas) and body water (aqueous) * Diffusion vs. Solubility: diffusion is not rate-limiting * Limited by physical process of dissolving in aqueous medium (cellular/interstitial fluids and blood plasma) The partition coefficient is unique trait for a given gas (i.e., chemical constant) - Partition coefficient reflects rate of absorption of gases/vapors * Low solubility gases: Perfusion-limited gases/vapors * High solubility gases: Ventilation-limited gases/vapors

Answer 28

Aerosols: xenobiotics dissolved in liquid droplets Particles: solids dispersed in air (e.g., smoke/smog, dust/asbestos, plant pollens) Deposition in the respiratory tract (upper vs. lower) is influenced by size (i.e., diameter) of particles Mucociliary escalator: alveolar macrophages phagocytose (“cell eating”) larger particles and transport them to the upper respiratory tract Alveolar dust plaques/nodules: alveolar macrophageinduced collagen fiber deposition resulting in long-term retention of particles in the lower respiratory tract Efficiency depends on the solubility or dissolution in lung fluids (i.e., the lower the solubility the longer the retention time) - The more soluble a compound is in the liquid phase, the less time it will spend being carried along by the gas

Answer 29

Two major layers of skin: epidermis (outer-most) and dermis (inner) Stratum corneum * Semi-solid outer surface * Most important barrier of skin * Limits absorption of most xenobiotics and loss of body water

Answer 30

Absorption directly through stratum corneum occurs via simple diffusion Penetration of xenobiotics is proportional to lipophilicity and inversely proportional to molecular weight Small highly lipophilic xenobiotics (e.g., organic solvents/oils) may be able to penetrate the stratum corneum readily - Molecules >400 Da exhibit poor percutaneous penetration) - Charged and polar xenobiotics do not penetrate directly through stratum corneum (however, appendages later) Absorption of xenobiotics is inversely related to thickness of stratum corneum layer - Thickness of stratum corneum in various regions of body surface: Palm > back of hand > forehead > Scrotum

Answer 31

Distribution is the systemic movement of xenobiotics within the body away between the site of absorption and target tissue - Requires the circulatory and lymphatic system - The rate of distribution is determined by three factors: 1) Blood flow 2) Transport from organ capillary beds into organ interstitial fluid 3) Affinity for target tissue Xenobiotics have the potential to distribute to different compartments of total body water * Plasma: liquid fraction of unclotted blood after removal of blood cells * Interstitial water: extracellular space in organs * Intracellular water: cytoplasm of cells

Answer 32

Sequestration in compartments can hinder distribution * Xenobiotics may have an affinity for tissue other than their target organ of toxicity Sequestered xenobiotics may persist in body for long durations (e.g., years) * May provide protection by diminishing distribution to target organ * May hinder drug therapy by ↓ potency/efficacy * May be released from sequestered site (delayed toxicity)

Answer 33

1) Plasma proteins 2) Body fat 3) Keratinized tissue/hair 4) Bone

Answer 34

Binding of xenobiotic is reversible * koff/kon determine the extent to which a xenobiotic is free - k on affinity higher k off affinity lower KD quantitative measure of binding affinity The lower the KD, the higher the affinity: kon > koff Plasma albumin is a receptor for many xenobiotics Lipophilicity is important chemical determinant of albumin binding affinity * The high the LogP, the lower the Kd Albumin is important for filtration Xenobiotics with higher affinity may outcompete for binding of xenobiotics with lower affinity Xenobiotic displacement of endogenous factor may cause toxicity

Answer 35

Made of adipocytes are fat storing cells in adipose tissue - Body fat is highly lipophilic Sequestration can occur over long time periods Reversible: mobilization of fat release xenobiotics Body fat level is an important factor in xenobiotic sequestration in adipose tissue - the more body fat the more sequestration

Answer 36

Selective bioaccumulation of xenobiotics * Arsenic, lead, mercury - bad metals that can accumulate Can provide a non-invasive biomarker for exposure to certain xenobiotics

Answer 37

Made of fibrous matrix of hydroxyapatite - Ca2+ (calcium), PO (phosphate) -, OH (hydroxide) Bone remodeling is continuously occurring naturally - Osteoclasts: bone breakdown via osteolysis - Osteoblasts: bone formation via mineralization - Osteoporosis: wasting (e.g., long term weightlessness) Sequestration of xenobiotics in bone tissue * Storage is can be long-term and reversible * Bone breakdown (resorption) can release sequestered xenobiotics * Exchange occurs at the bone interface Xenobiotics in bone lead (Pb) and fluoride (F) - lead can be toxic under certain conditions - fluoride can be directly toxic

Answer 38

CNS - brain, spinal cord, retina BBB - Specialized endothelial cells, Continuous form of endothelial layer, Linked by tight junctions between cells, Maintains the interstitial ionic environment No paracellular transport - no filtration occurs in brain Dyes (very small molecules) penetrate the interstitial space of most tissues except the brain/spinal cord Electrical resistance: measure of leakiness of endothelium Partitioning of xenobiotics into brain * Increases with increased lipid solubility * Decreases with ionization/polarity To get into the brain needs simple diffusion or solute carrier protiens - lipophilicity is important ABC transporters * Lumenal side of the endothelium * Extrude xenobiotics (even those with high lipophilicity) The BBB is a serious limitation on efficacy drug therapies for treatment of CNS maladies

Answer 39

Once a gas is dissolved in the liquid phase of the lungs, it can move by diffusion down its concentration gradient. However, it must be soluble in the liquid phase first. This is why solubility is rate limiting. For a gas with low solubility in liquid, the concentration gradient will not be very strong because the concentration difference between the gas phase and liquid phase is small. This is why low solubility gases depend on blood perfusion, which carries what does dissolve away from the lungs. This will maintain the small concentration gradient so the gas can continue to dissolve in the liquid. Thus gases with low solubility are perfusion-limited.

Answer 40

Paracellular transport is not possible through the epithelial cell barrier (and some endothelial cell barriers) because of the tight junctions between the cells. In other words, filtration is not an option. Of course, highly lipophilic xenobiotics can pass through the epithelial cell barrier by transcellular transport down their concentration gradient. On the other hand, xenobiotics with low lipophilicity (low solubility in the organic phase of the membrane) can still pass through these barriers via transcellular transport but require protein transports to do so. The GI tract epithelial cell layer possess these solute carrier proteins to aid in the transcellular transport of xenobiotics (and nutrients) with low lipophilicity.

Answer 41

The more soluble the gas in the liquid the higher concentration of gas there is in the lungs are ventilation limited Less soluble needs high perfusion rate (blood flow) for the gas to continue to be absorbed The coefficient of solubility of gases is expressed as the ratio of the concentration of the gas in liquid (i.e. blood) divided by the concentration of gas in air [liquid phase]/[gas phase]. The greater the ratio (i.e., >1), the more soluble the gas is in liquid, and the higher the concentration of gas in the lung tissue (i.e., saturation of the tissue occurs at a much higher concentration of gas than lower solubility gases). Such gases are ventilation limited (i.e., how much is absorbed depends on how fast we can breathe in the gas). On the other hand, the lower the ratio (e.g., <1), the less soluble the gas is in liquid. In this case, saturation of the tissue will occur at a low concentration and prevent further increases in the concentration in the tissue. The lower the solubility the gas, the lower the tissue concentration will be when this occurs. Such gases will require a high perfusion rate (blood flow) for the gas to continue to be absorbed because the blood will carry the absorbed gas away maintaining a low tissue concentration (i.e., reduce the possibility of saturation).

Toxicology Exam 1 Flashcards

(65 cards)