Midterm 1 Flashcards
(243 cards)
1
Q
Ebers Papyrus
A
circa. 1500 B.C. - contains information regarding poisons
2
Q
Book of Job
A
circa 1400 B.C- speaks of poison arrows
3
Q
Hippocrates
A
circa. 400 BC- toxicology principles pertaining to bioavailability in therpay
4
Q
the dose makes the posion
A
paracelsus
5
Q
what is toxicology
A
the study of adverse effects of chemicals or poisons on living organisms
- combines the elements of biology and chemistry with many other disciplines to help us understand the effects of chemicals on living organisms
6
Q
what is a poison
A
any agent capable of producing a deletrious response in a biological system
7
Q
what is a toxicologist
A
studies the adverse health effects and assesses the probability of their occurrence
- develop new and better methods
- design and carry out controlled studies to determine the conditions in which substances can be used safely
- assess the probability or likelihood of health hazards
8
Q
areas of toxicology
A
- clinical toxicology
- forensic toxicology
- regulatory toxicology
- developmental toxicology
- reproductive toxicology
- molecular toxicology
- environmental toxicology
9
Q
poison
A
any agent capable of producing a deleterious response in a biological system
10
Q
toxicity
A
refers to “the degree to which something is poisonous.” Denotes the amount of a substance that can produce a deleterious effects
11
Q
toxicants OR xenobiotics
A
toxic substances that are man-made or result from human (anthropogenic) activity.
12
Q
toxin
A
usually refers to a toxic substance made by living organisms including reptiles, insects, plants, and microorganisms
- usually a protein
- examples: bacterial toxins, mushroom toxins animal toxins (venom)
13
Q
dose-response relationship
A
- a type of correlative relationship between the characteristics of exposure to a chemical and the spectrum of effects caused by the chemical
14
Q
dose response curve
A
a type of graph used to describe the effect of exposure to a chemical or toxic substance upon an organism
15
Q
ED50, TF50, LD50
A
therapeutic effect, toxic effect, lethal effect
16
Q
additive effect of chemical mixture
A
the combination of two chemicals produces an effect that is equal to their individual effects added together
2+2=4
17
Q
synergism effects of chemical mixtures
A
indicates that the combined effect of exposures to two or more chemicals is greater than the sum of their individual effects
2+4=10
18
Q
potentiation effect of chemical mixtures
A
happens when one chemical that is not toxic causes another chemical to become more toxic
0+2=4
19
Q
antagonism effect of chemical mixtures
A
two or more chemical administered together interfere with each other’s actions
- protective effect against each other
2+4=3
20
Q
acute duration of exposure
A
an exposure less than 24 hours
21
Q
subacute duration of exposre
A
exposure for one month or less
22
Q
subchronic duration of exposure
A
exposure for 1-3 motnhs
23
Q
chronic duration of exposure
A
exposure for more than three months
24
Q
in vivo testing
A
alive organisms exposed purposively or accidental - whole organism
25
in vitro testing
cells derived from human, animal, or plants sources
- this would include testing an individual organ because its not the whole organism
26
in silico testing
predictions by computer modelling or simulation
27
volatile organic chemicals
- Boiling points below 250 C and up to 260 C
- Have vapor pressure above 0.01 kPa
- must be careful with boiling point definitions - many compounds with high boiling points begin to degrade before they boil
- the lower the boiling point the more volatile the compound
28
important volatile organics- fules
gasoline, kerosene, diesel, BTEX
29
Important volatile organics solvents
- non-polar
-polar
-chlorinated
- non-polar: pentane, hexane, iso-octane, toluene
- polar: ether, pyridine, acetone, MIBK
- Chlorinated: methylchloride, methylene chloride, chloroform, trichloroethane, tetrachlorethylene, PCE, etc.
30
important volatile organics refrigerants
- CFC
- HFC
31
Important Volatile Organics
- volatiles may be significant contributors to air and groundwater pollution
- vapors escape during use and often react to form secondary oxidation products, which contribute to smog
- even non-polar small molecules have appreciable water solubility and can reach groundwater
32
semivolatile organics
- boiling points above 240-260 C but below 400 C
- vapor pressures in the range of 10^-14 - 10^-4 atm
33
important semivolatile organics- natural flavors and aromas
- cinnamic aldehyde/acid, etc.
- pyrethrum, putracene, musks
34
important semivolatile organics- polycyclic aromatic hydrocarbons (PAHs)
produced from: combustion (pyrogenic), biosynthesis involving terpen condensation (biogenic or petrogenic)
- the more aromatics in a fuel source the more PAHs during combustion
- the more rings the higher the KoW- the higher this number the more the lipophilic
35
important semivolatile organics - perfluorinated organs (PFOA, PFOSs, etc.)
36
important semivolatile organics- chlorinated hydrocarbons
- OC pesticides, PCBs
37
important semivolatile organics- pesticides
- organophosphorus, carbamate
- pyrethroids, phenoxyacids
38
important semivolatile organics- industrial products and byproducts
flants retardants, dioxins, musks
39
what are PCBs
polychlorinated biphenyls
- used as dielectric fluids
- prevent electric arcing in high voltage applications
- due to a large difference in chlorine content PCBs have a range of water solubility, vapor pressure, Kow or Koc, toxicity
- chloride is highly reactive but its connection to this molecule creates a highly stable compound- major issue with bioaccumulation because of how stable Cl is- no longer produce PCBs due to the toxicity of bioaccumulation
40
health effects of PCBs
- can cause cancer in animals and are designated as probable human carcinogens
- may impact the immune system, reproductive system, and children's intellectual development
- may limit the development of immune responses to the epstein-barr virus and other viral and bacterial infections
41
PCDDs
polychlorodibenxodioxins
- produced from burning chlorinated aromatics and syntheses of functionalized polychlorinated aromatics
- stable, persistent, and bioaccumulate within the food chain
- the more chlorides the more stable the molecule however that does not necessarily correlate to toxicity
42
what does the terms dioxins refer to
a family of chemical compounds that are unintentional biproducts of certain industrial, non-industrial and natural processes, usually involving combustion
43
organophosphorus insecticides
- act as neurotoxicants
- analogues of nerve agents
- central phosphorus with 2 to 3 O-alkyl functions
- normally found in agricultural areas, lawn-scapes, and homes
- little volatility, slight water solubility, and tightly bound to soils
44
what are organophosphorus insecticides also know as
anticholinesterase agents
45
signs and symptoms of organophosphorus insecticides poisoning
- toxicity occurs via inhibition of acetylcholinesterase AChE
- enzyme responsible for the destruction and termination of the biological activity of the neural transmitter acetylcholine ACh
GI symptoms, cardiovascular symptoms, premature aging
- intermediate syndrome; paralytic condition appearing 24 to 96 hours after the acute cholinergic crisis
- muscle weakness involving muscles innervated by the cranial nerves as well as those of the limbs
46
organochlorine pesticides
- low vapor pressure and water solubilities
- HIGH Kow
- VERY bioaccumulative
- no longer produced in large quantities
- now considered legacy pollutants
- derived from chlorinated hydrocarbons
- characteristically stable and fat-soluble; persist in the environment
- associated with suppression of the immune system and cancer
47
biotransformation, distribution, and storage of organochlorine pesticides
- proceeds exceptionally slow
- highly lipophilic and sequestered in body tissue with high lipid content
- small amounts equilibrate with blood and are degraded and/or excreted
48
carbamate insecticides
- derivatives of carbamic acid
- normally secondary amine
- interact with cholinesterase in similar fashion to organophosphorus OP compounds
- shorter half life than OP
- dissipate quickly in the environment as a result of breaking down into other substances- this is because they don't have chlorides
49
examples of carbamate insecticides
- carbyl
- aldicarb
- fenoxycarb
- propoxur
- metam sodium
50
perfluorinated compounds
- PFOS and PFOA
- PFOS- stain resistant
- PFOA- nonstick cookware
- problematic because they are largely nonreactive and mimic lipids in our body
- long chain or short chain; short chain has fewer than 6 carbons and used as an alternate to long chain PFAS
- short chain are less bioaccumulative but still persistent in the environment and can be highly mobile in water, leading to concerns of contamination
- nicknamed the forever chemicals due to resistance to environmental degradation
- exposure has been linked to cancer, thyroid dysfunction, immune impacts, and developmental issues in children
51
silanes and silyl ethers
- VERY important in current environmental evaluations
- lubricants in drilling or hydraulic fracturing fluids
- cosmetics and personal care products
52
brominated compounds
- PolyBrominated Biphenyls and PolyBrominatedDiphenyl Ethers
- contain bromine and are commonly used as flame retardants in a variety of products.
- these compounds persist in the environment an accumulate in living organisms posing potential health risks - disrupt endocrine systems, impact neurological development, and contribute to ecological toxicity
53
N-nitro and nitroso compounds
- reactive precursors, industrial chemicals, explosives, tobacco smoke
- N-nitro compounds can be reduced to nitroso compounds
- N-nitroso compounds are carcinogenic
54
toxic metals
- a heavy metal has a high atomic weight with a specific gravity that exceeds the specific gravity of water by five or more times at 4 C
55
CERCLA priority list of hazardous substances
Comprehensive Environmental Response, Compensation, and Liability Act of 1980
- top 20 hazardous substances
56
difference in dose response curve between toxic metals and essential metals
- essential metals have a u-shaped curve
- toxic metals have just a sigmoidal curve
57
arsenic
- used in pesticides, wood preservatives, and in manufacturing processes
- byproduct of refining gold and other metals
- exposure from ingestion or inhalation
- effects include- skin, bladder, kidney and liver cancer when ingested; lung cancer when inhaled; peripheral vascular disease; cerebrovascular disease; and adverse pregnancy outcomes
58
cadmium
- osteoporosis in women
- height loss in men
- kidney damage
- elevated blood pressure
- cardiovascular disease
- itai-itai disease
59
chromium
- naturally occurring element in the earth's crust
- most common forms are chromium 0, chromium III, and chromium VI
60
difference between Chromium III and Chromium VI
chromium III - essential nutrient
chromium VI- classified as a carcinogen
61
lead
- sources if env. lead include leaded gasoline, tap water from pipes, and painted surfaces in older buildings
- common source of household exposure is imported pottery used in food service
62
mercury
- naturally occurring metal, highly toxic
- released into environment as byproduct of industrial processes
- at low levels it represents a hazard because it gets deposited in beds of lakes, rivers, and other bodies of water
- bioaccumulation causes mercury to become more concentrated in aquatic invertebrates
63
steps of toxicity
1. delivery
2. reaction
3. dysfunction
4. repair or disrepair
64
what traits favor delivery
absorption, distribution toward target, reabsorption, toxication
65
what traits reduce delivery
presystemic elimination, distribution away from target, excretion, detoxication
66
absorption vs. pre-systemic elimination
absorption- transfer of chemical from the site of exposure into systemic circulation
presystemic elimination-
67
mechanisms of facilitating distribution to a target
- porosity of the capillary endothelium
- specialized transport across the plasma membrane
- accumulation in cell organelles
- reversible intracellular binding
68
mechanisms opposing distribution to a target
- binding to plasma proteins
- specialized barriers
- distribution to storage sites
- association with intracellular binding proteins
- export from cells
69
excretion
excretion is the removal of xenobiotics from the blood and their return to the external environment- this is a physical mechanism
- route and speed of excretion depends largely on the physiochemical properties of the toxicant
- kidney and liver and the major excretion organs
- highly hydrophilic chemicals are removed efficiently
70
reabsorption
kidney- renal tubules-tubular cells-peritubular capillaries
- increases the the intratubular concentration and the residence time
- highly dependent upon lipid solubility of the chemical
liver- toxicants delivered by biliary, gastric, intestinal excretion, secretion by salivary glands, and exocrine pancreas diffuse across intestinal mucosa.
- from bile happens only if the compound is made more lipophilic or are highly lipophilic in the beginning
71
toxication
biotransformation to a harmful product (metabolic activation)
- electrophiles
- free radicals
- nucleophiles
- redox-active reactants
- most reactive are electrophiles and free radicals
72
detoxification
biotransformation that eliminate the ultimate toxicant or prevent its formation
73
detoxification of a molecule with no functional groups
done in two phases- functional group is introduced and then an endogenous acid is added by a transferase
74
detoxification of a molecule with nucelophiles
conjugation at the nucleophilic functional group
75
detoxification of molecule with electrophiles
conjugation with the nucleophile glutathione sometimes facilitated by glutathione S-transferase
76
detoxification of molecules with free radicals
antioxidants
77
toxicity reaction
toxicity is mediated by a reaction of the ultimate toxicant with a target molecule
- a series of secondary biochemical events occurs
78
1. attributes of target:
-
-
-
2. reaction types
-
-
-
3. outcomes
-
-
-
1. attributes of target:
- reactivity
- accessibility
- critical function
2. reaction types
- noncovalent binding
- covalent binding
- hydrogen abstraction
- electron transfer
- enzymatic reaction
79
all ________ compounds are potential targets for toxicants
all endogenous compounds are potential targets for toxicants
80
most prevalent and toxicologically relevant target molecules are
nucleic acids, proteins, and membranes
81
first target for reactive metabolites is
- enzyme responsible for their production or the adjacent intracellular structures
82
non-covalent reactions
the formation of hydrogen and ionic bonds typically is involved in the interaction of toxicants with targets
- membrane receptors, intracellular receptors, ion channels, enzymes
- usually reversible
83
covalent
permanently alters the endogenous molecules
- common with electrophiles and radical cations
84
hydrogen abstraction reaction
neutral free radicals can readily abstract H atoms from endogenous compounds
- can form cross links with DNA via removal of H from free amino acids or residues in proteins
85
electron transfer reaction
exchange of electrons to oxidize or reduce other molecules
86
enzymatic reactions
toxics can act enzymatically on specific target proteins
87
dysfunction of target molecules
some toxicants mimic endogenous ligands, but more commonly they inhibit functions of target molecules
88
destruction of target molecules
toxicants can alter primary structure of endogenous molecules by means of cross-linking and fragmentation
89
neoantigen formation
covalent binding of xenobiotics or their metabolites to protein may evoke an immune responses
90
dysfunction
- the reaction of toxicants with a target molecule may result in impaired cellular function
- there are certain programs that determine whether cells undergo division, differentiation, or apoptosis
- if the target molecule is involved in the cells internal maintenance the resultant insult may compromise survival of the cell
91
dysregulation of gene expression
it may occur at elements that are:
1. directly responsible for transcription
2. at components of the intracellular signal transduction pathways
3. at the synthesis, storage, or release of the extracellular signaling molecules
92
dysregulation of transcription
xenobiotics alter the activation of TFs interrupting the transcription of genetic info from DNA to mRNA
93
dysregulation of signal transduction
chemicals may cause aberrant signal transduction most often by altering protein phosphorylation and occasionally by interfering GTPase activity of G proteins
- disrupting normal protein-protein interactions
- establishing abnormal interactions
- altering the synthesis or degradation of signaling proteins
94
dysregulation of extracellular signal production
xenobiotics alter the hormone circuits
95
dysregulation of excitable cells
- release of neurotransmitters and contractions are controlled by transmitters and modulators that synthesized and released by adjacent neurons
- these can caused by chemical through alterations in concentration of neurotransmitters, receptor function, intracellular signal transduction, and signal terminating process
96
three biochemical disorders chemicals inflicting cell death may initiate
- ATP depletion
- sustained rise in intracellular Ca2+
- overproduction of ROS/RNS
97
Necrosis
- abrupt increase in mitochondrial inner membrane permeability (MPT)
- opening or create protein pore in mitochondrial membranes
98
necrotic cell vs apoptotic cell
- necrotic cells swell and lyses
- apoptotic cells shrink and break into fragments that are phagocytosed - very controlled
99
what is key in cell death mechanisms
release of cytochrome c
- loss will block ATP synthesis, increase the formation of superoxide anion, and potentially push the cell towards necrosis
100
molecular repair
- chemical alterations can be reversed
- removal an reinsertion of new units can occur
- chemically altered DNA
- total degradation and re-synthesis can occur
101
types of molecular repair
- repair of proteins, lipids
- repair of DNA, which includes: direct repair; excision repair, recombinant repair
102
tissue repair
in tissues with cells capable of multiplying damage is reversed by apoptosis or necrosis of the injured cell and regeneration of the tissue by proliferation
- types of tissue repair: replacement of lost cells by mitosis; replacement of the extracellular matrix
103
side reactions to tissue repair
- inflammation: in response to tissue damage cytokines are secreted which can produce free radicals
- altered protein synthesis: cytokines (secreted in response to tissue damage) act on cell surface receptors to increase or decrease the transcriptional activity of genes that code for proteins (acute phase proteins)
- generalized reactions: cytokines released can trigger fever by altering the temp set point of the hypothalamus
104
what happens if tissue repair fails
- tissue necrosis: can occur if molecular repair mechanisms are inefficient or if molecular damage is not readily reversible
- fibrosis: condition characterized by excess deposition of an extracellular matrix with abnormal composition
- extracellular matrix production is not turned off after repair
- carcinogenesis: insufficient function of various repair mechanisms
105
step 1 of tissue repair: failure of DNA repaier
1. mutation, the initiation event
2. damaged DNA can cause adduct formation
3. The mutation is passed to the daughter strand during replication
4. some altered genes can produce mutant proteins that reprogram cells for multiplication
5. the result is a tumor
106
step 2 of tissue repair: failure of apoptosis
1. promotes mutation and clonal growth
2. inhibition of apoptosis is detrimental because mutations and clonal expansion of pre-neoplastic cells is facilitated
107
step 3 of tissue repair: failure to terminate proliferation
- promotion of mutation, proto-oncogene expression, and clonal growth occurs
- increases the probability of mutations
- overproduced proto-oncogenes proteins may cooperate with oncogene proteins to facilitate neoplastic transformation of cells
- cell-cell communication via gap junctions and intercellular adhesions through cadherins are disrupted contributing to invasiveness of a tumor
108
why is it that the same dose of two or more chemicals may lead to vastly different concentrations in a particular target organ
disposition
109
factors that affect disposition
- fraction or rate of absorption
- distribution of a toxicant decreasing or increasing its toxicity
- biotransformation into something less or more toxic thus affecting concentration and toxicity at a target site: metabolism or biotransformation
- speed at which a chemical is eliminated from an organism; lower concentration less toxicity: excretion
110
main barriers to chemical
skin, lungs, and alimentary canal
111
cell membranes as a barrier
toxicants usually go through membranes of cells
- epithelium of skin
- thin cell layers of lungs and GI tract
- capillary endothelium
- target organ or tissue cells
112
types of passage through the cell membrane
1. passive transport- no energy expended; simple diffusion, filtration, facilitated diffusion
2. specialized transport- requires energy
113
toxicants through passive transport: simple diffusion
majority of toxicants pass through the cell membrane this way
- small hydrophilic molecules
- hydrophobic molecules diffuse across the lipid domain of membranes via transcellular diffusion
the rate of transport across membranes correlates with lipid solubility
- ionized form of weak organic acids or bases: low lipid solubiltiy- does not readily permeate through the lipid domain of the membrane
- non-ionized forms are more lipid soluble: diffuse across membrane at a rate proportional to its solubilityf
114
passive transport: filtration
water in bulk flowing across the porous membrane
- when this happens any solute small enough to pass through pores flows with it
main difference in membranes is pore size:
- large pore size: renal glomeruli (molecular weight of about 60,000)
- small pore size (most cells): pass of molecules with molecular weight no more than a few hundred daltons
115
facilitated diffusion
carrier-mediated transport the exhibits the properties of active transport except that the substrate is not moved against an electrochemical/concentration gradient and the transport process does not require input of energy
116
characteristics of an active transport system
1. chemicals are moved against electrochemical or concentration gradients
2. saturated at high substrate concentrations and thus exhibits transport maximum
3. selective for certain structural features of a chemical
4. potential for competitive between compounds that are transported by the same transporter
5. requires expenditure of energy, so metabolic inhibitors block the transport process
117
special transport processes
- endocytosis: phagocytosis and pinocytosis
118
absorption
the process by which toxicants cross body membranes and enter the bloodstream
119
enteral administration
all routes pertaining to the alimentary system
120
parenteral administration
all other routes
- intravenous, intraperitoneal, intramuscular, and subcutaneous
121
absorption in the gi tract
- one of the most important sites of toxicant absorption
- contents can be considered exterior to the body
- toxicants in the gi tract typically do not cause systematic injury until they are absorbed
- absorption can take place anywhere along the gi tract
- factors affecting absorption of weak organic acids or bases: mass action law, surface area, blood flow rate
- has specialized transport system for absorption of nutrients and electrolytes
122
which active transport system decreases the absorption of xenobiotics
mdr transporter localized in enterocytes
123
what does the amount entering systematic circulation after oral administration depend on
- the absorbed amount into gi cells
- biotransformation by gi cells
- extraction by the liver into the bile- first pass effect
124
absorption in the lungs
- gases and vapors: absorption of inhaled gases takes place mainly in the lungs
- when a gas makes it to the lung: gas molecules diffuse from alveolar space into the blood, dissolve until equilibrium is reached between blood and alveolar space, when equilibrium is reached the ratio is called the blood-gas partition coefficient
125
what is the rate of absorption in the lungs dependent on
gases solubility ratio
- concentration in blood/concentration in gas
- before saturation or at saturation
-
126
gases with a very LOW solubility ratio are _________ limited
perfusion limited
127
gases with a very HIGH solubility ratio are ________ limited
ventilation limited
128
what are the major characteristics that effect absorption after exposure to aerosols
aerosol size and water solubility
129
absorption in skin
toxicant must pass through the epidermis or the appendages of the skin
130
what is the rate determining layer in the skin
stratum corneum
131
parenteral administration routes
- intraperitoneal: into body cavity
- subcutaneous: into layer of skin below the dermis and epidermis
- intramuscular: into the muscle
- intravenous: directly into the bloodstream
132
distribution
after a chemical enters the body it may undergo translocation throughout the body
- rate of distribution is determined primarily by blood flow and rate of diffusion out of capillary bed into the cells and tissues
- final distribution depends on affinity of a xenobiotic for various tissues
133
volume of distribution
concentration of a toxicant in blood depends largely on its volume of distribution
- total body water: intracellular water and extracellular water
- complex with critical factors involved: binding to and dissolution in various storage sites in body
- some toxicants have restricted distribution whereas others pass rapidly through cell membranes and are distributed
134
storage of toxicants in tissues
the free fraction of chemical in the body is at equilibrium NOT what is in storage sites.
- binding to or dissolving in certain body constituents greatly alters the distribution of a xenobiotic
toxicants can be concentrated in a tissue that may or may not be its site of toxic action
- as biotransformation or excretion occurs, more toxicant is released from the storage site
135
plasma proteins as storage
several plasma proteins bind xenobiotics as well as physiologic constituents: albumin, transferrin, globulins, and lipoproteins can bind a large number of compounds
- xenobiotics and compete and displace endogenous compounds that are bound to plasma proteins
- the protein-ligan interactions occur primarily as a result of hydrophobic forces, hydrogen bonding, and van der waals forces
- after binding to a plasma protein, a toxicant is not immediately available for distribution into extravascular space or filtration by the kidney
136
liver and kidney as storage
- liver and kidney have a high capacity for binding a multitude of chemicals
- these two organs concentrate more toxicant than all other organs combined
- proteins such as ligandins and metallothioneins have a high affinity for many organic compounds and metals
137
fat as storage
- concentrates highly lipophilic toxicants
- the storage lowers the concentration in the target organ- toxicity of compound would be less severe in an obese person than in a lean individual
- should a rapid immobilization of fat occur, there would be a sudden increase in the concentration of the chemical in the blood and thus in the target organ
138
bone as storage
skeletal uptakes of xenobiotics is essentially a surface chemistry phenomenon
- this is mostly due to metal; calcium carbonate can be replaced by metal
- xchange taking place between bone surfaces of hydroxyapatite crystals and extracellular fluid
- deposition and reversible storage of toxicants in bone are dynamic and may or may not be detremintal
139
examples of bone as storage
- lead; not toxic to the actual bone
- chronic effects of fluoride deposition- skeletal fluorosis
- radioactive strontium- osteosarcoma
140
blood-brain barrier
less permeable than most other areas of the body
141
what are the four major anatomic and physiologic reasons why some toxicants will not readily enter the CNS
1. capillary endothelial cells of the CNS are tightly joined leaving few/no pore between the cells
2. brain capillary endothelial cells contain ATP-dependent mdr proteins that exude some chemicals back into the blood
3. capillaries in the CNS are to a large extent surrounded by glial cell processes- astrocytes
4. protein concentration in the interstitial fluid of the CNS is much lower than that in other body fluids, limiting the movement of water insoluble compounds
142
what two things are important determinants to the rate of entry of a compound into the CNS
lipid solubility and the degree of ionization
143
what type of lipid solubility enhances the rate of entrance into the CNS
increased lipid solubility enhances
144
does ionization increase or decrease rate of entrance into the CNS
ionization decreases the rate of entrance
145
how can some xenobiotics enter the CNS
some xenobiotics can enter the CNS through carrier-mediated processes
146
passage of toxicants across the placenta
- placental barrier consists of at most 6 layers of cells. Interposed between fetal and maternal circulation
- CONTAINS BIOTRANSOFORMATION ENZYMES and active transport systems to protect fetus- very high metabolism
147
prior to elimination most xenobiotics have to be biotransformed to what before they can be excreted into urine
more water soluble product
- toxicants can be found in sweat, tears, saliva, and breast milk
148
urinary excretion
toxic compounds are excreted into urine via the same mechanism the kidney uses to remove end products of intermediary metabolism from the body
- glomerular filtration, tubular excretion, active tubular secretion
- toxicants with a high lipid/water partition coefficient and reabsorbed efficiently
149
what is the main factor that affects the rate of filtration in the kidneys
the degree of protein binding
- too large to pass through the pores of the glomeruli
150
what kind of compounds are excreted with urine
polar compounds and ions
151
active secretion in the kidney
- families of transporters- oat, oct, mdr, and mrp
- organic cation transporter and peptide transporter reabsorb chemicals from the tubular lumen
- protein bound toxicants are available for active transport
- a toxicant binding small proteins can be carried into the proximal tubule cells and exert toxicity
152
fecal excretion; major pathway of elimination of
- non absorbed ingesta
- biliary excretion- most important contributing source to the fecal excretion of xenobiotics and their metabolites
- intestinal excretion- rapid exfoliation of intestinal cells may contribute
- intestinal wall and flora- 30-42 percent of fecal dry matter originates form bacteria
153
biliary excretion
most important contributing source to the fecal excretion of xenobiotics and metabolites
- liver can extract xenobiotics from blood and prevent distribution
- xenobiotics in the intestine with bile can be directly excreted or can enter entero-hepatic circulation
- transporters in the liver move toxicants from plasma to live and from liver to the bile
154
intestinal wall and flora
- chemicals can be altered profoundly by bacteria before excretion with feces
- biotransformation via intestinal flora favors reabsorption rather than excretion
- we can alter the bacteria population in our intestines via probiotics and antibiotics
155
lung excretion- exhalation
happens for substances in the gas phase and volatiles that exist at body temp
- simple diffusion predominates
- elimination of gases is roughly inversely proportional to the rate of absorption
156
excretion via cerebrospinal fluid
all compounds can leave the CNS with bulk flow of CFS
157
excretion via milk
toxicants can be passed from mother to nursing offspring and compounds can be passed from cows to people
- 3-4 percent of milk is fat so lipid soluble xenobiotics will diffuse into the mammary gland and excreted into the milk
158
what is biotransformation
the metabolic conversion of endogenous and xenobiotic chemicals to more water soluble compounds
- changes made from those favoring absorption to favor excretion
- exception to this rule is volatile compounds being eliminated via exhalation
159
biotransformation does what to the pharmacologic effects
terminates pharmacologic effects and usually lessens the toxicity
- sometimes biotransformation can lead to a more toxic compound
160
what do enzymes catalyzing biotransformation reactions often determine
the intensity and duration of action of drugs
- they play a key role in chemical toxicity and chemical tumorigenesis
161
phases of biotransformation
xenobiotic, lipophilic--- phase 1 activation --- reactive intermediate --- phase 2 conjugation ---- conjugate --- excretion, water soluble
162
phase 1 of biotransformation
1. introduction of functional group through hydrolysis, reduction, or oxidation
2. hydrophilicity increases slightly
3. may inactivate or activate original compound
4. major player is CYP system in conjugation with NADPH
- location of reaction is smooth er; short rxn
163
phase 2 of biotransformation
1. conjugation with endogenous molecules
2. hydrophilicity increases substantially
3. neutralization of active metabolic intermediates
4. facilitation of elimination
- location of this reaction is usually the cytoplasm
- this is the longer reaction phase
164
xenobiotic transforming enzymes
1. biotransformation is accomplished by a limited number of enzymes with a broad substrate specificity
2. synthesis of some of these enzymes is triggered by the xenobiotics and others are expressed constitutively via enzyme induction
3. xenobiotic-endobiotic biotransformation- no clear distinction
- sometimes this can also impact things like hormone regulation etc. because your body cant distinct between multiple things catalyzed by the same thing
4. structure of a biotransforming enzyme may differ among individuals which can give rise to differences in rates of transformation
5. balance between activation and detoxification is often key determinant of chemical toxicity
6. stereochemical aspects play important role btwn xenobiotic and biotransformation
165
balance between what two things is often a key determinant of chemical toxicity
activation and detoxification
166
what aspect plays an important role between a xenobiotic and biotransformation enzyme
stereochemical aspects
- stereoisomer conversions
- different biotransformation rates between stereoisomers
167
what tissues contain biotransformation enzymes
biotransformation enzymes are distributed widely throughout the body
- liver has the richest source of enzymes that catalyze biotransformation reactions; but they exist in most tissues
- intestinal microflora play an important role on biotransformation of certain xenobiotics
168
what parts of the cell do biotransformation enzymes mostly exist in
primarily in the er- microsomes, and the soluble fraction of the cytoplasm- cytosol
169
phase 1 reaction - hydrolysis
- hydrolysis of carboxylic acid esters, amides, and thioesters is catalyzed largely by carboxylesterases and by two esterases
- no cofactor needed
- esterases play an important role in limiting the toxicity of orgranophosphates
170
what type of reactions happen in phase 1
hydrolysis, reduction, or oxidation
171
epoxide hydrolase
- hydrolysis
- catalyzes the trans-addition of water to alkene epoxides and arene oxides
- inducible enzyme in the liver microsomes
172
azo- and nitro- reduction
- reduction reaction
- cofactor needed- NADPH-quinone oxidoreductase
- catalyzed by intestinal microflora and two liver enzymes; CYPS450, require NADPH and are inhibited by oxygen
- azo-reduction- double bonded Nitrogens to two NH2 groups
- nitro-reduction- NO group to one NH2 group
173
quinone reduction
- reduction reaction
- quinones are oxidized derivatives of aromatic compounds
- quinone reduction to hydroquinones by cytosolic flavoprotein NADPH quinone oxidorediuctases without oxygen
- microsomal NADPH-cytochrome P450 reductase- enzyme
174
dehalogenation
- reduction reaction
3 main mechanisms for removing halogens from aliphatic xenobiotics
1. reductive - H replaces halogen
2. oxidative- halogen and H on adjacent carbon atom replaced with double bonded O
3. double dehalogenation- 2 halogens on adjacent carbon atoms, form double bonded carbons
175
alcohol dehydrogenase- ADH
oxidation reaction
- four major classes
- alcohols to aldehydes
- genetic polymorphism
- inhibited by ranitidine, cimetidine, asprin
176
aldehyde dehydrogenase- ALDH
oxidation reaction
- aldehydes to carboxylic acids with NAD as the cofactor
- ALDH1 and ALDH2 reduce NAD
- ALDH3 reduces both NAD and NADP
- ALDH2 is a mitochondrial enzyme responsible for oxidizing simple aldehydes
177
flavin-containing monooxygenases FMO
oxidation reaction
- generally results in detoxification of xenobiotics nucleophilic nitrogen, sulfur and phosphorus heteroatom
- five microsomal enzymes that require NADPH and O2
178
cytochrome P450
oxidation reaction
- microsomal enzyme ranking first among phase 1 enzymes with respect to catalytic versatility
- CYP 1, 2, 3 perform drug metabolism
- highly inducible
- have multiple alleles- polymorphism
179
where is the highest concentration of CP450 found
highest concentration is found in the hepatic ER; microsome
180
what is the basic reaction catalyzed by CYP450
monooxygenation or one atom of oxygen into a substrate
- the oxygen atom is reduced to water with the reducing equivalents derived from NADPH
181
generally, CYP450 requires what for catalytic activity
a second enzyme
- exception to the rule thromboxane synthase and prostacyclin synthase
182
where are CYP450s and NADPH cytochrome P450 reductase are imbedded in
the phospholipid bilayer of the ER
- this facilitates the interaction
183
what is the first part pf cytochrome P450 oxidation reaction
activation of oxygen
- after the binding of the substrate the P450 enzyme, Heme iron is reduced from ferric to ferrous by addition of single electron from NADPH-cytochrome P450
184
what is the final part of cytochrome P450 oxidation
substrate oxidation
- abstraction of hydrogen atom or electron from the substrate
- oxygen rebound
185
release of oxidized substrate returns cytochrome P450 to what state
initial state
- if there is an interruption then we get super anion or hydrogen peroxide
186
what type of reactions does cytochrome P450 catalyze
- hydroxylation of an aliphatic or aromatic carbon
- epoxidation of a double bond
- heteroatom oxygenation and N-hydroxylation
- Heteroatom dealkylation
- oxidative group transfer
- cleavage esters
- dehydrogenation
187
variation in activity levels of cytochrome P450 are dependent on what
- genetic polymorphism
- environmental factors; inducers, inhibitors, disease
- multiple P450's can catalyze the same reaction- the lowest Km predominates
- a single P450 can catalyze multiple pathways
188
three approaches to reaction phenotyping CYP450
- correlation analysis
- chemical antibody inhibition
- biotransformation by purified or recombinant human P450 enzymes
189
correlation analysis
measuring the rate of xenobiotic metabolism by several samples of human liver microsomes and correlating reaction rates with the variation in the level or activity of the individual P450 enzymes in the same microsomal samples
190
chemical antibody inhibition
evaluates the effects of known P450 enzyme inhibitors or inhibitory antibodies on the metabolism of xenobiotic by human liver microsomes
191
biotransformation by purified or recombinant human P450 enzymes
this establishes whether a particular enzyme cannot biotransform a xenobiotice
192
inhibition of cytochrome P450
- competitive- one drug metabolized by the same enzyme
- competitive but inhibitor is not a substrate for the affected P450 enzyme
- non-competitive inhibition by covalent binding to P450 - mechanism based and irreversible
193
induction of cytochrome P450
may increase the activation of pro-carcinogens to DNA-reactive metabolites. Competitive but inhibitor is not a substrate for the affected P450 enzyme
- leading to increased tumor formation
- little evidence that p450 induction enhances the incidence or multiplicity of tumors caused by known chemical carcinogens
can cause pharmocokinetic tolerance by which larger drug doses must be administered to achieve therapeutic blood levels
- increased drug biotransformation
194
glucuronidation
conjugation reaction
- major phase 2 pathway in mammals
- UDP-glucuronyltransferase, catalyst, forms O-, N-, S-, C- glucuronides
- cofactor is UDP-glucuronic acid
- the carboxylic acid moiety of glucuronic acid promotes excretion because it increases the aqueous solubility of the xenobiotic and it is recognized by the biliary and renal anion transport systems allowing secretion into urine and bile
195
glucuronides of xenobiotics are substrates for what that are present in intestinal microflora
beta-glucuronidases
- the intestinal enzyme can release the aglycone, which undergoes enterohepatic circulation and delays the elimination of the xenobiotic
196
sulfation
conjugation reaction
- four sulfotransferases, catalyst, are widely distributed in liver cytosol
- cofactor is 3'-phosphoadenosine-5'-phosphosulfate- PAPS
- high affinity, low capacity pathway
- aryl sulfatases in gut microflora remove sulfate groups; enterohepatic recycling occurs delaying elimination
197
what is sulfation capacity limited by
capacity is limited by low PAPS levels
198
methylation
conjugation reaction
- common, minor pathway, that decreases water solubility - masks functional groups that might otherwise be conjugated by other phase two compounds
- enzymes responsible are methyltransferases
- co-factor is S-adenosylmethionine (SAM)
199
acetylation
conjugation reaction
- major route of biotransformation for aromatic amines, hydrazines- converted to aromatic amides
- generally decreases water solubility
- N-actetyltransferase (NAT) is the enzyme
- acetylcoA is the cofactor
200
aminoacid conjugation
conjugation reaction
- alternative to glucuronidation
Two main pathways depending on the amino acid
- substrates- bile acids, NSAIDs
- metabolic activation results in serine or proline N-esters of hydroxylamines that that are unstable and degrade to reactivate electrophiles
201
glutathione conjugation
conjugation reaction
- enormous array of substrates
- Glutathione-S-transferase catalyzes conjugation with glutathione- localized in the cytoplasm and ER
- Glutathione is tripeptide of glycine, cysteine, glutamic acid -cofactor
- substrates are hydrophobic, contain an electrophilic atom and react non-enzymatically with glutathione
- excretion of conjugates- excreted intact in bile, converted to acids in kidney excreted in urine
- GSH is also a cofactor
202
why is conjugation with GSH an important reaction
electrophiles are potentially toxic species that can bind to critical nucleophiles
203
how can conjugation with glutathione activate xenobiotics and what results
activates xenobiotics and enhances toxicity by becoming more toxic by releasing a toxic metabolite, by being inherently toxic or by being degraded to a toxic metabolite
204
what is toxicokinetics
the study of modeling and mathematical description of the time course of disposition of xenobiotics in the whole organisms
- purpose- to quantify ADME and provide an exposure framework for risk assessment
205
classic model of toxicant
- chemicals move through the body as if there were one or two compartments that might have no apparent physiologic or anatomic reality
206
physiologically-based models
body is represented as a series of mass balance equations that describe each organ or issue on the basis of physiologic considerations
207
toxicodynamics vs toxicokinetics
toxicodynamics- explores what a compound does to the organism
toxicokinetics- explores what the organism does to the compound
208
compartmental pharmacokinetic model (classic model)
- body is viewed as distinct compartments, which are interconnected by rate constants
- modeling is viewed as empiric, and compartments do not directly correspond to tissues
209
physiologically based pharmacokinetic model (PBPK model)
- body is viewed as grouped tissue compartments which are interconnected by blood flows
- modeling is mechanistic, and compartments are defined by physiologic volumes and partition coefficients
210
the central compartment in classic toxicokinetics is connected to one or more peripheral compartments that represent what
represent tissues that equilibrate more slowly with chemicals
211
advantages of classic toxicokinetics
- predicting plasma chemical concentration at different doses
- establishing time course of chemical in plasma and tissues
- extent of chemical accumulation with multiple doses
- determining effective doses and dose regimens in toxicity studies
212
disadvantages of classic toxicokinetics
- cannot interpret compartments biologically
- many ADME processes are interconnected
- cannot make predictions beyond the experiment being described
- cannot incorporate everything else we know about biology
213
compounds whose toxicokinetics can be described with a one-compartment model, ______ or _______ between blood and tissues relative to the rate of elimination
equilibrate rapidly or mix uniformly
214
what type of curve does the two compartment model yield
semilogarithmic plot
215
what does the semilogarithmic plot imply
- there is more than one dispositional phase- no uniform mixing and no rapid equilibrium
- the chemical requires a longer time for tissue concentrations to reach equilibrium with concentration in the plasma
- multicompartment analysis is required
216
elimination in one-compartment models occurs through what process
first order process
- concentrations are not high enough to saturate the elimination process
- with elimination we are concerned with what fraction of the chemical remains in the body overtime
217
what is the apparent volume of distribution
- proportionality constant that relates the total amount of chemical in the body to the concentration of a xenobiotic in plasma
- the apparent space into which an amount of chemical is distributed in the body to result in a given plasma concentration
- describes how a toxic compound/drug is distributed to the rest of the body compared to plasma
218
what does a low volume of distribution imply and what does a high volume of distribution
low volume of distribution means compound stays in the plasma, this is good since rest of the body is where toxicity happens
high volume of distribution means not much in plasma but there's a lot rest of the body
219
what is clearance
describes the rate of chemical elimination from the body in terms of the volume of fluid containing chemical that is cleared per unit time
- characterizes the overall removal efficiency of a chemical; high values of clearance is efficient rapid removal; low values of clearance is less efficient, slow removal
- total body clearance is defined as the sum of clearances of individual organs
220
what is half life
- the time required for the blood or plasma chemical concentration to decrease by one half
- it is a hybrid parameter reflecting volume of distribution and clearance
- inversely related to constant of elimination
221
saturation toxicokinetics
- when the concentration of a chemical in the body is higher than the Km, the rate of elimination is no longer proportional to the dose
- non-linear toxicokinetics
222
why is the the transition from first from first order kinetics to saturation kinetics important
it can lead to prolonged residency time and increased concentration at the target site of action
223
non-linear toxicokinetics
- the decline in the levels of the chemicals in the body is not exponential
- AUC is not proportional to the dose
- volume of distribution, clearance, equilibrium constant, half-life changes with increasing dose
- composition of excretory products changes quantitatively or qualitatively with dose
- competitive inhibition by other chemicals that are biotransformed or actively transported by the same enzyme system occurs
- dose response curves show a non-proportional change in response with an increasing dose starting at the dose level at which saturation effects become evident
224
bioavailability
- the fraction of the dose absorbed systematically
- it can be determined using different doses as long as the compound does not display dose-dependent or saturable kinetics
- pharamacokinetic data after intravenous administration are used as the reference from which to compare extravascular absorption
- bioavailability ranges between 0 and 1
- complete absorption is F=1
- incomplete absorption F is less than 1
- the amount of chemical that reaches systematic circulation is of critical importance in determining toxicity
225
factors affecting systemic availability
- limited absorption after ingestion
- intestinal-liver first-pass effect
- mode of formulation
226
advantages of physiologically-based toxicokinetic models
- can provide the time course of distribution of xenobiotics to any organ or tissue
- they allow estimation of the effects of changing physiologic parameters on tissue concentrations
- the same model can predict the toxicokinetics of chemicals across species by means if allometric scalings
- complex dosing regimes and saturable processes such as metabolism and binding are accommodated easily
227
what can a compartment be in the toxicology models
- functional or anatomic portion of an organ
- single blood vessel in a tissue section
- discrete organ
- widely distributed tissue
228
4 types of information required for toxicology
1. anatomical
2. physiological
3. thermodynamic
4. transport
229
anatomical parameter
physical description of various compartments
- size is typically expressed as volume
- volume for each compartment must be known
230
physiological parameters
encompass various processes
- must know blood flow rate and cardiac output
- for routes of inhalation exposure you must know alveolar ventilation rate
231
thermodynamic parameters
- used to relate total concentration of xenobiotic in a tissue, to concentration of free xenobiotic in that tissue
- free concentration is available for binding, metabolism, or removal from a tissue by blood
- partitioning into tissue
232
what are two important assumptions for thermodynamic parameters
- total and free concentrations are in equilibrium
- only free xenobiotic can enter and leave tissues
233
what is partitioning into tissues
- dependent on the composition of the tissue and independent of the concentration of the xenobiotic
- total c=cf x partition coefficient
234
partition coefficient or distribution coefficient
- ratio of concentrations of a compound in a mixture of two immiscible phases at equilirbium
- ratio is a measure of the difference in solubility of the compound in these two phases
235
transport parameter
passage of a xenobiotic across a biological membrane
- diffusion
236
how can passage of a xenobiotic membrane occur by
- passive diffusion
- carrier mediated transport
- facilitated transport
- combination of processes
237
diffusion can occur across what
- the blood capillary membrane
- the cell membrane
238
what are the two limiting conditions for transport
- perfusion limited
- diffusion limited
239
perfusion limited compartments
- happens when cell membrane permeability coefficient for a particular xenobiotic is much greater than the blood flow rate to the tissue
- rate of xenobiotic uptake is limited by rate at which the blood containing the xenobiotic arrives at the tissue
240
diffusion limited compartments
uptake that is governed by cell membrane permeability and total membrane area
- when the flux of xenobiotic across cell membranes is slow compared to blood flow to the tissue
- implying that PA is small compared with the blood flow
xenobiotic concentrations in the interstitial and vascular spaces are in equilibrium
- this makes up the extracellular subcompartment
- uptake from incoming blood is flow limited
241
assumptions from lung compartment
1. ventilation is continuous
2. airways function as inert tubes carrying vapor to the gas exchange region
3. diffusion vapor across the lung cell and capillary walls is perfusion-limited
4. ALL xenobiotic disappearing from inspired air appears in arterial blood
5. vapor in the alveolar air and arterial blood within the lung compartment are in rapid equilibrium
242
specialized compartment- liver
- considered flow limited
- include processes for metabolic elimination
- must consider saturable metabolism is the physiologic model of a liver compartment; this allows for the simulation of chemical disposition across a range of doses
243
