Shared Flashcard Set

Details

Toxicology
Exam 2
96
Biochemistry
Undergraduate 3
10/12/2015

Additional Biochemistry Flashcards


 

 


 

Cards

Term
Disposition:
Definition
– Absorption
– Distribution
– Biotransformation
– Excretion
( fundamental factor that contributes to potential toxicity)
Term
toxicity is dependent on..?
Definition
the conc. at the site of action
Term
Conc. at the site of action
Definition
• usually proportional to “internal dose” at the site of action
• target tissue, cell or molecule
depends on absorption, distribution and excretion
• (biotransformation)
• determine the potential for adverse events occurring
Term
Initial barriers
Definition
separate higher organisms from environmental toxicants:
– skin
– lungs
– alimentary canal: mouth to anus
– exclude caustic or corrosive agents that act topically
• acid, base, salt & oxidizer
Term
Factors affecting disposition of xenobiotic/toxicant:
Definition
insufficient conc. at the target site:
• poor absorption or low rate of absorption
• poor distribution
• rapid biotransformation to less toxic form
• rapid excretion (elimination)
– “the dose make the poison”
Term
Absorption
Definition
transfer of a toxicant from exposure site into systemic circulation
Term
Distribution
Definition
entry of a toxicant into internal body fluid (blood stream); translocates throughout the fluid compartments of the body
Term
Elimination
Definition
removal of absorbed toxicant from systemic circulation though excretion, metabolism and storage
Term
Excretion
Definition
removal of systemic toxicant through excretory processes
– renal (kidneys), fecal (GI tract), pulmonary (volatile substances)
Term
Cell Types
Definition
stratified epithelium of skin/mouth
– simple squamous epithelia of lung/kidney glomeruli/ blood vessels/capillaries (endothelial)
– cuboidal epithelia of kidney tubules
– simple columnar epithelia (cilia) of GI tract
Term
Plasma Membranes (PM)
Definition
phospholipid bilayer
– phospholipid (variants)
– glycolipid (lipids with carbohydrates)
– cholesterol
– proteins
semifluid
•  unsaturated fatty acids abundance
•  facilitate active and passive transport
•  differentially permeable
Proteins inserted/embedded
Term
Phospholipid
Definition
amphiphilic (7–9 nm thick)
•  hydrophilic polar heads: outer/inner surface (has phosphate group and glycerol)
•  hydrophobic trails: inward – hydrophobic inner space (kinks due to cis double bond)
Term
Transmembrane proteins
Definition
– transverse the entire lipid bilayer
– receptors
– aqueous pores
– ion channels
– transporters
Term
Simple diffusion
Definition
(passive transport)
– many toxicants
– no energy expenditure
– Fick’s Law: down the conc. gradient
– transcellular diffusion
– paracellular diffusion
Term
transcellular diffusion
Definition
• crosses lipid domain
• cross apical and basal membrane
– and basolateral
• small lipophilic/hydrophobic molecul
Term
paracellular diffusion
Definition
• “aqueous pores”
• between cells – intercellular space
• small hydrophilic molecules
• < 600 Da (600 g/mol)
• smaller: rapid diffusion (ethanol)
Term
Rate of diffusion pertaining to large organic molecules
Definition
correlates with lipophilicity
– pertains to large organic molecules
– lipid solubility
– degrees of lipophilicit
Term
Partition Coefficient (P)
Definition
– represents the lipophilic/hydrophilic nature of compound
– function of Gibbs energy of transfer from water to octanol
– thermodynamic tendency of neutral compounds to partition preferential between 2 media
Term
Lipid solubility
Definition
– determined by octanol/water partition coefficient P
– ratio of compound in organic and aqueous phases under equilibrium conditions



P = [X]org / [X]aq
– expresses as Log P
– Physiochemical parameter to assess potential membrane permeability
Term
Negative LogP
Definition
Lead acetate Log P = - 0.63
negative: low lipid solubility (some amino acids)
Term
Positive LogP
Definition
TCDD Log P = 7.05
positive: high lipid solubility
Term
Uses of LogP
Definition
Pharmacology (drug design)
Toxicology
Bioconcentration
Soil/sediment accumulation (sorption)
Term
Weak Organic Acids and Bases
Definition
– ionize in water (Arrhenius’ theory)
– Acid ionize -> H+
– Base ionize -> OH-
– Ionized forms: Low lipid solubility
– slow permeation through the lipid domain of PM
– low MW: aqueous pores (slow/insufficient)
– nonionized forms: some lipid solubility, lipid domain PM
Term
ionization constant:
Definition
pH at which 50% ionized à pKa and pKb
pH = - Log [H+]
pKa = - Log Ka smaller pKa = stronger the acid
Ka = [A-][H3O+]/[AH][H2O]
pKa + pKb = 14
Kw = [H3O+][OH-] = 1.0×10−14 M2 at 25ºC
Term
Henderson-Hasselbalch Equations
Definition
– derive pH as a function of pKa in biological system
pH = pKa + Log [ionized]/[nonionized]
pH = pKa - Log [nonionized]/[ionized]
extend of ionization
acid: pKa – pH = log [nonionized]/[ionized]
base: pKa – pH = log [ionized]/[nonionized]
degree of ionization depends on its pka & ph of soln
Term
Degree of Ionization of Benzoic acid and Aniline
Definition
•  Benzoic acid:
– readily translocates through PM from an acidic env.
•  Aniline:
– readily translocates through PM from a basic env.
Term
Passive diffusion requires certain conditions
Definition
– concentration gradient
– lipid soluble toxicant
– toxicant must be in nonionized form
Term
Filtration
Definition
(simple diffusion)
– bulk movement of water across membrane pores
• channels
• aqueous pores (fenestrate endothelium)
• aquaporins
– small solutes pass though pores with water
– passage though pores = filtrations
– osmotic pressure (force)
Term
Renal glomeruli
Definition
• primary site of filtration
• aqueous pores = 70 nm
• passage of small molecules (~ 60 kDa)
Term
Special Transport
Definition
– large compounds
– xenobiotics, amino acids, nucleic acids
• restricted from diffusion/filtration/aqueous pores
• specialized transport systems
• membrane-associated transporters
• facilitate chemical disposition
• often against conc. gradient
• influx and efflux transporters
• 500 genes involving specialized PM transporters
Term
Facilitated Diffusion
Definition
(special transport)
– carrier-mediated transport system
– movement down a conc. or electrochemical gradient
– no energy expenditure
– high conc. may saturate transporters
– exclude metabolic poisons (active transport)
Term
ex. for facilitated diffusion
Definition
nutrients
• glucose
– from GI tract across basolateral PM of intestinal epithelium
– from plasma into red blood cells
– from blood into CNS
Term
Xenobiotic Transporters
Definition
(special transport)
•  Carrier-mediated transport system
•  ~ 5% of all human genes are transport-related
•  influx and efflux of xenobiotics
•  many are bidirectional
•  Two main categories / two major super families
 Active transport
– energy-dependent transport
– ATP-binding cassett (ABC) transporters
– largely efflux
 Facilitated transport
– Solute carriers (SLCs)
– largely influx
Term
Active Transport
Definition
(special transport)
•  movement across PM against conc. and electrochemical gradients
•  requires expenditure of energy
•  selective for certain structural features
•  subjected to competitive inhibition by chemical antagonist (congeners = biochemical variant)
•  competition with other chemicals using the same transporter
•  subjected to saturation at high substrate conc.
•  may be inhibited by metabolic poisons
•  metabolic inhibitors can block the transport process
Term
first identified active transport protein ex.
Definition
Phosphoglycoprotein
– overexpressed in tumor cells that showed resistance to anticancer drug
– Multidrug Resistance (MDR) to the cell
– coined: P-glycoprotein (P-gp or MDR1)
– gene name MDR1
– transporter functions as an efflux pump
– exudes cytotoxic drugs out of the tumor cell
– protect cell from drug-mediated destruction
Term
MDR1
Definition
(aka ABCB1)
– first member of large super family of transport proteins known as
Ø ATP-binding cassette (ABC) transporters
Term
ATP-binding cassette (ABC) transporters
Definition
7 subfamilies of ABC transported (A–G)
• involve 49 human genes
– first large family of xenobiotic transporters
– requires binding and hydrolysis of ATP to function
– two structural domains (repeated)
• Hydrophobic membrane spanning lipid domain (MSD)
• Hydrophilic intracellular nucleotide binding domain (NBD) -> ATP binding and hydrolysis site
Term
Many ABC transporters
Definition
are vital to maintaining homeostasis of endogenous substrates
– Absorption and elimination of many xenobiotics
• GI tract absorption
• Bile/urine elimination
– Maintain barrier functions
• BBB
• Maternal-fetal barrier
Term
ABCA1
Definition
egulates cholesterol in cell
• mediate its efflux from liver
Term
ABCB4
Definition
transport phospholipid substrates
• Phosphatidylethanolamines (PE) are a class of phospholipids found in biological membranes
Term
ABCC subfamily
Definition
(C subfamily):
– aka multiresistant drug protein (MRD) family
• multidrug resistant-associated protein
– five domains
Term
ABCC1
Definition
(MRD1):
• isolated from multidrug resistant cells
• excrete chemicals from cells
Term
MRD2 and MRD3:
Definition
important in efflux of xenobiotic metabolites
• conjugated to UDP-glucoronic acid or glutathione
Term
ABCG subfamily
Definition
(G subfamily):
– Breast cancer resistance protein BCRP
• isolated from breast cancer cell lines
• also expressed in normal tissue
• efflux of endogenous and xenobiotic sulfate conjugates
• expressed in stem cells
• protection from xenobiotics
Term
Solute carriers
Definition
(SLCs superfamily)
– facilitated transporters
– 43 SLC gene families
– ~ 300 genes
– Disposition of endogenous compounds
• glucose, neurotransmitter, nucleotides, peptides, essential metals
– xenobiotic disposition: organic anions/cations
– Expressed in body’s epithelium
Term
Types of SLCs
Definition
– Organic Anion Transporting Polypeptide ATP
– Organic Anion Transporters OATs
– Organic Cation Transporters OCTs
– Peptide transporters PEPTs
– Multidrug and Toxin Extrusion MATE
Term
Organic Anion Transporting Peptides
(substrate)
Definition
– OATPs major groups in this family
– substrate: large hydrophobic organic anions
– amphipathic
– MW >350 DA
– bile acids
– conjugated to steroids, hormones, peptides, mushroom toxins, drugs (antibiotics/cancer drugs)
Term
OATPs (largely influx pumps)
Definition
allow bidirectional movement of solutes
– important in hepatic uptake of xenobiotics
– liver anion uptake
– expressed: intestines, brain, liver, kidneys, testes
Term
OATPs
Definition
transport of organic anions, cations, and neutral compounds (Na+ independent)
– anion exchange mechanism
– cellular influx of organic compound is coupled with efflux of HCO3-, glutathione/conjugates
– affected by pH (pH increase/increase activity)
12 domains
Term
Organic anion transporter (substrate)
Definition
substrates: smaller, more hydrophilic organic anions
Term
OATs (mechanism)
Definition
– anion exchange mechanism:
– sodium-independent
– important role in renal uptake of anions
– generally facilitated diffusion
– transport substrate against electrochemical gradient
– exchange for intracellular dicarboxylates
transport organic anions, predominately in kidney
Term
OATs (tissue)
Definition
kidneys, skeletal muscles, brain, placenta
Term
OATs (organic-carboxylate exchangers)
Definition
• α-ketoglutartae
• gradient maintained by Na+/K+ ATPase
• antiviral/anticancer drugs
– associated with drug-drug interactions
Term
Organic-cation transporter
Definition
– substrate: organic cations
– important role in liver uptake of xenobiotics (also kidneys)
– novel OCTs (OCTNs) transport exogenous cations and endogenous compounds
– generally facilitated diffusion
– transport against electrochemical gradient of the transported cation
– tissue: liver-specific, weak expression in heart skeletal muscles, kidneys, brain, placenta
• broad range of organic cations
• affinity for substrate do depend on ionization
• endogenous/exogenous substrates, drugs, neurotransmitters, antiviral drugs
Term
Peptide transporters PEPTs
Definition
– di and tri- peptide transport
– various drugs and toxicants
(SLCs)
Term
Multidrug and Toxin Extrusion MATE transporters
Definition
– cation efflux pumps
– liver and kidneys
(SLCs)
Term
Xenobiotic Transporters: Additional transport processes
Definition
•  Phagocytosis
•  Pinocytosis (receptor mediated)
•  Lungs: alveoli (nanoparticles)
•  Blood: reticuloendothelial system of liver and spleen
Term
Absorption of Toxicants
Definition
•  Cross body membranes and enters bloodstream
•  Main sites:
– GI tract,
– lungs and
– skin
Term
GI tract (absorption)
Definition
– most important
– environmental toxins enter with food
– absorption à entire GI: mouth-anus
– sublingually / rectal suppositories
– chemical and physical properties of toxicants
– Gastric juices pH 2 / Small intestine pH 6
most substances is absorbed by diffusion
• lipid-soluble substances more effective

• simple diffusion
• weak organic acids/bases nonionized forms (neutral)
• lipid-soluble form
Term
GI tract (other
Definition
mass action law, surface area, blood flow rate
– absorption is a dynamic process: blood removes toxicant once it’s absorbed
• keeps conc. low
• small intestine: villi/microvilli à increase surface area 600-fold à facilitate absorption
Term
GI tract (transport system)
Definition
Carrier-mediated transport systems
• nutrients/electrolytes
• iron: rapidly absorbed my GI mucosa cells by transport protein
• divalent metal transporter 1 or DMT1
• protein-iron complex (ferritin) stores iron à iron is only released once blood iron conc. drops à continued absorption to replenish stored iron
Specialized Transporters for Nutrients
• xenobiotics compete/interact
– Special Xenobiotic Transporters
• SLC transporters/carriers
Term
GI tract (epithelium)
Definition
– Absorption of particles and particulate matter
• particle size
• inversely related to absorption
– increase in size (diameter)/decrease in absorption
– oral exposure of metallic mercury less toxic
• pinocytosis ( > 20 um)
• nanoparticles
• lipid-solubility and ionization is less important
Term
GI tract Other factors that influence absorption
Definition
• pH
• presence of food and digestive enzymes
• bile acids
• gut microflora (bacteria)
• GI tract permeability and motility
Term
GI tract (chemical resistance/lack of resistance)
Definition
hydrolysis by stomach acids, biotransformation by enzymes, modified by microflora à new compound with altered toxicity compared to original
Term
GI tract (microflora)
Definition
• influence absorption and toxicity
• Clostridium and Eubacterium species
• reduction of nitroaromatic compounds (nitrobenzene to aromatic amine)
• nitroreductases
• produce toxic carcinogenic aromatic amines
Term
Chelates (EDTA)
Definition
increase lipid solubility of metals (lead)
• absorption of the metal complex
Term
GI tract
– Systemic circulation is determined by:
Definition
• Absorption and biotransformation by GI tract
• Extraction of xenobiotics by liver into bile
• Transporters affect influx and efflux
Term
Presystemic elimination
Definition
(first-pass effect) = removal before entrance into systemic circulation
Term
Chemical with a high first-pass effect
Definition
have lower absorption
• rapid elimination
Term
Lungs
Definition
Inhalation exposure, Respiratory absorption
•  Airborne contaminants
•  The lungs are an important entry point for toxic gases, solvents, aerosols, and particulates.
Term
Why are lungs so absorbent?
Definition
Pulmonary tissue is highly vascularized and has a large surface area (approximately 100 m2 in adults) for toxicant absorption.

Toxicant
Term
Toxicant absorption from the respiratory system
Definition
nasopharyngeal-> tracheobronchial-> alveolar-> lymph (can enter the blood from any of these organs)
Term
Examples of inhalation exposure and symptoms
Definition
Occupational Hazards
 CO poisoning (acute exposure)
• CDC: Flu-like: headache, dizziness, weakness, upset stomach, vomiting, chest pain, and confusion.
• reversible and irreversible (neurological)
• lethal: pass out and die
• fetal hypoxia
• everyone is at risk
Silicosis: silica dust (chronic exposure)
• CDC: pneumoconiosis: swelling in the lungs (restrictive lung disease) and chest lymph nodes
• pulmonary nodules
• irreversible
• other adverse effects: lung cancer, pulmonary tuberculosis, and airways diseases
Term
Major groups of inhaled toxicants
Definition
– gases: carbon monoxide, nitrogen dioxide, sulfur dioxide
– Vapors of volatile and volatilizable liquids: benzene and CCl4
• volatile organic compounds: VOC
– Aerosols and particles
Term
Gases and Vapors
Definition
Vapor: a gas of substance that can exist as a solid or a liquid at atmospheric pressure and ambient temp.
– liq. -> gas/vapor -> evaporation
– solid -> gas -> sublimation
Term
vapor pressure
Definition
pressure excreted by vapors above its liquid (closed system)
Term
high vapor pressure
Definition
high tendency to evaporate
Term
high vapor pressure at RT
Definition
volatile liquid
Term
absorption of toxicant through inhalation
Definition
largely lungs (surface area)
Term
nasal mucosa
Definition
trap water-soluble vapors
  react with cellular components
Term
Inhalation exposure
Definition
lung protection (scrubber)
  nasal adverse effect
  formaldehyde: nasal turbinates-tumors in rats
Term
Factors of inhalation exposure
Definition
ionized molecules: very low volatility -> low conc. in normal ambient air
  short distance of diffusion: pneumocytes type I are a thin layer/gas exchange
  Rapid removal from lungs by blood (surface area and extensive capillaries)
Term
Gas/Vapor Absorption
Definition
§  diffusion from alveolar space into capillaries
§  gas dissolve in blood
§  physical process: dissolving
Term
Process of diffusion of inhaled gas
Definition
Result is that the gas partition between media
lung<->blood<->tissue
(lung<->blood: absorptive phase)
(blood<->tissue: distribution phase)
Inhaled gas continuous to dissolve in blood until there is an equilibrium between gas in blood and gas in alveolar space

§  At equilibrium ratio is constant





[gas]blood/ [gas]alveolar space
§  This solubility ratio = blood-to-gas partition coef.

Lung
Term
[gas]blood/ [gas]alveolar space
Definition
lung<->blood
gas-blood-partition coefficient
§ unique value for each gas

§  Ratio is constant and varies according to
§  Henry’s law

Lung
Term
Henry’s law
Definition
amount of gas dissolved in liquid is proportional to the partial vapor pressure of the gas at any conc. before or at saturation
Ptotal = Pgas1 + Pgas2 +…+ Pgasn
§  pressure gradient
§  higher inhaled conc. -> higher partial pressure -> higher blood conc.
§  ratio remains constant unless saturation occurs
[gas]blood/ [gas]alveolar space
Term
At equilibrium (for inhalation)
Definition
rate of transfer for alveolar space to blood = rate of removal by blood from alveolar space
Term
blood-to-gas partition coefficient examples
Definition
Chloroform (CHCl3) = 20 (large value)
§  very soluble in blood
§ requires large amount of gas to dissolve in blood before partial pressure in blood is increases and gas exist blood and enter other tissue cell membranes
Ethylene (CH2CH2) = 0.14 (very low)
à blood is quickly saturated
§  requires small amount of gas to dissolve in blood before partial pressure in blood is increases and gas exist blood and enter other tissue (brain)
§  a smaller percentage of ethylene is removed from alveolar space into blood
Term
Rate of absorption in lungs depends on...
Definition
depends on toxicant’s solubility ratio at equilibrium


[gas]blood/ [gas]alveolar space

§  The more soluble the toxin is in blood, the more will dissolve by the time equilibrium is reached
Term
High solubility ratio
Definition
(blood/gas) > 1
à rapid transfer during single respiratory cycle à little remain in alveolar space before next inhalation
Term
Low solubility ratio
Definition
(blood/gas) < 1
à quick saturation à slow transfer à high conc. remain in alveolar space
Term
Increased respiratory rate
Definition
increase uptake of compounds with low solubility – gets removed from site of equilibrium
Term
the ionization potential (weak organic acids/ bases) and lipid solubility for respiratory are...
Definition
less important of respiratory absorption compared to intestinal and percutaneous absorption
Term
Gases with high solubility
Definition
ventilation-limited
§  rate and depth of respiration determines the extend of distribution
Term
Gases with low solubility
Definition
perfusion limited
§  here the rate of blood flow is the primary factor for distribution
Term
way lungs limit systemic circulation
Definition
Lungs can be site of biotransformation and or elimination
Supporting users have an ad free experience!