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PED3011 Toxicology > Skin > Flashcards

Skin Flashcards

1
Q

What is the function of the skin

A

Barrier
Controls water loss
Temperature regulation
Sensation
Controls

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2
Q

What is the structure of the skin

A

Epidermis: outer layer
Dermis: fibroblasts and connective tissues
Hyperdermis: adipose tissues and major vessels

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3
Q

Describe the epidermis

A

Basal layer contains keratinocytes
Cell differentiation - increasing keratinisation
Antigen presenting langerhans cells that patrol spaces between keratinocytes

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4
Q

Discover the stratum corneum

A

Physical barrier
Outermost layer of epidermis
Several layers of highly keratinised, dead cells
Endpoint of epidermal differentiation

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5
Q

Describe keratinised cells

A

No nucleus or organelles
Contains DNA
Constantly renewed and shed

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6
Q

What are the 2 routes chemicals can take through the skin

A

Transcellular
Intracellular

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7
Q

What happens to chemicals on the stratum corneum

A

Lost by desquamation due to constant regeneration

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8
Q

Describe the bricks and mortar model

A

Bricks: corneocyte
Mortar: lipid

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9
Q

Describe ceramides

A

Constituents of the skins ‘mortar’
Long alkyl chains that are very unsaturated
More stable than phospholipids
Covalently connected to outer envelope

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10
Q

Describe absorption through the skin

A

Stratum corneum is the major barrier
Permeability varies with site
Damage increases permeability

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11
Q

Describe the perfusion of the skin

A

Not highly perfused compared to lung, liver, kidney etc
Absorbed material maybe removed in dermal blood supply

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12
Q

Describe intracellular absorption

A

Through the cells of the stratum corneum

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13
Q

Describe extracellular absorption

A

Around the cells through the lipid matrix

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14
Q

What is the major factor influencing absorption of a particular chemical

A

Lipophilicity
Highly lipophillic chemicals enter stratum corneum but have hard time leaving it

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15
Q

What does a low LogP show

A

Chemical is water soluble and will find it difficult to enter stratum corneum but easy to exit

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16
Q

What are the other factors that influences absorption

A

Form of deposition
Concentration
Temperature/ humidity/occlusion
Anatomical site
Damage
Metabolism/binding

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17
Q

How is occlusion an influencing factor

A

Prevents water from getting into it or preventing surface dose from evaporating

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18
Q

What similarities are there between human volunteers and experimental animals when testing percutaneous absorption

A

Expensive
Difficult to obtain ethical approval (easier in animals)
Biological monitoring required

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19
Q

What is the gold standard in in vivo studies of percutaneous absorption

A

Human volunteers
Traditional animals models have more permeable skin but domestic pig is best

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20
Q

Describe in vitro model systems of percutaneous absorption

A

Diffusion cells, perfused skin flaps etc
Easier to conduct and interpret
Full thickness, dermatomed and epidermal membranes

Still not as good as ex vivo humans

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21
Q

How does a static diffusion cell work

A

2 chambers separated by a membrane
The product to be tested is in the donor component (top)
The bottom chamber has fluids from which samples can be taken and analysed

This determines the amount of ‘active’ that permeates through the membrane at point time

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22
Q

What part of the skin is experimented on

A

Superficial plexus isn’t usually perfused so the epidermis and a little bit of the dermis are used

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23
Q

How is the absorption of chemicals described within in vivo experiments

A

Dislodgeable: can we washed off does not enter the skin
Absorbable: can get into the skin (epidermis + dermis)
Absorbed: has reached the receptor fluid (systemic circulation)

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24
Q

If a chemical is detected in the stratum corneum only can it be classed as absorbable

A

No due to its constant regeneration
Only if the chemical is toxic like a pesticide

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25
What is a finite dose
Simulation of real life exposure Chemical that gets inside is limited by how much goes intro skin Absorption rate changes constantly
26
How can absorption be limited in a finite dose experiment
By dose By vehicle ( no vehicle = no conc gradient)
27
What kind of exposure times are used in a finite dose
6-10hr to mimic a working day Up to 18hr for a leave on products Wash off products 2mins - 30 days (hair dyes)
28
Describe an infinite dose
Not representative of real life Absorption not limited by dose or vehicle = reaches a steady state after a lag time Exposure time is usually 24hr
29
When can flux, lag time and permeability coefficient be measured
Infinite doses The conc applied stays relatively constant w time
30
Describe the metabolism of xenobiotics in the skin
Chemical ———-> activated chemical ———> elimination I I Binding to macromolecules I I Toxicity
31
Where are CYP450s located in the skin
Basal keratinocytes and hair follicles
32
Describe the role of CYP450s in the skin
Present at low activates when expressed -> little effect on absorption but can cause toxicity
33
What CYP450 is more expressed in the skin than the liver
2S1
34
Describe esterases in the skin
Cytosolic and microsomal Present in epidermis and dermis
35
How do esterases affect drug metabolism in the skin
Influence absorption by reducing lipophilicity Exploited for transdermal deliver of ester pro-drugs
36
Describe alcohol and aldehyde dehydrogenase
Cytosolic and mitochondrial May influence toxicity
37
Describe transferases in the skin
Detoxify and have higher activity than P450s Affect availability, not percutaneous absorption
38
Describe NAD(P)H quinone reductases in the skin
Activity similar to liver Detoxify quinines Prevent oxidative stress
39
What are examples of local topical toxicity
Corrosion Contact urticarial Physical dermatitis Irritation Immune reactions
40
How is systemic and dermal toxicity linked
Dermal absorption can lead to systemic toxicity Skin toxicity derived from systemically delivered drug
41
Describe contact dermatitis
Erythema, scaling and thickening Many possible causative routes by many agents
42
What are the different causative routes that could lead to contact dermatitis
Direct damage to cells = release of cytokines Local inflammation Can be delayed or immediate Doesn’t require previous exposure
43
What is the proposed mechanism of action based on surfactants that lead to contact dermatitis
Stimulate IL-1a release = stimulate release of IL6 and IL8, phospholipase-a2 and TNFa -> lead to cellular changes = symptoms
44
What is the proposed mechanism of action that membrane damaging irritants appear to work in contact dermatitis
Do not appear to work solely via the release of IL-1a Potentially operate through a ROS mechanism
45
Describe allergic contact dermatitis
IgE mediated, phase 2 response
46
Describe the induction phase of allergic contact dermatitis
Haptenisation -> complete allergens bind to proteins on Langerhans cells Allergens are presented on Langerhans cells Directed to lymph nodes by mediators T-cells bind to surface-bound, processed antigen on Langerhans cell = systemic release of activated T-cells
47
Describe the elicitation phase in allergic contact dermatitis
Allergen reacts with circulating sensitised T-lymphocyte when allergen enters viable dermatitis
48
What is the difference between a hapten, prohapten and prehapten
Hapten: passes SC and binds to protein to form an immunogen Prehapten: is activated to a hapten before the SC where it binds to protein to form an immunogen Prohapten: passes SC and then is activated to a haven’t where it binds to protein to form an immunogen
49
Name a few tests for skin sensitisers
Murine local lymph node assay Peptide reactivity Activation of keratinocytes and dendritic cells
50
Describe the murine local lymph node assay
In vivo method Measures the sensitisation phase No longer permissible for new cosmetics
51
Describe the direct peptide reactivity assay
‘In tubo’ test Measures depletion of model peptides containing nucleophilic residues Test chemical incubated with peptides containing cysteine or lysine Analysis via HPLC UV
52
Why are prohaptens difficult to detect
No cells = no enzymes to activate prohapens -> hapten Pretreatment with peroxidases has been proposed - could overestimate the detection of prohaptens
53
Describe the role of Keap1 and Nrf2 in the cell
Absence of chemicals SH groups on Nrf2keap remain as SH If Nrf2 detaches from Keap1 it is ubiquinated
54
Describe the role of Keap1 and Nrf2 in the cell when there are electrophiles or ROS present
SH groups react with chemicals or become cross linked = release of Nrf2 without ubiquitantion Nrf2 translocates to nucleus and binds to MAF and ARE = transcription of genes in response to chemical/ROS effects
55
Describe the KeratinoSens assay
HaCat cell line trasnfected with constructed with ARE, SV40 promoter and luciferase gene If no ROS or electrophile, Nrf2keap remains -> Nrf2 does not enter nucleus = no txn of luciferase
56
What does a positive result look like in the KeratinoSens assay
If ROS or electrophile present Nrf2 binds to ARE = txn of luciferase gene When ATP and luciferen present = visible light measures in luminometer
57
Describe the KeratinoSens Assay
Metabolically competent Some evidence that it can detect prohaptens Not as good as skin S9 fraction
58
Describe the h-CLAT assay
Monitors expression of CD86 and CD54 on the surface of THP-1 cells Assessment of skin sensitisation potential of chemicals
59
What is CD86 expression a marker of
Allergens
60
What does the expression of the marker proteins CD86 and CD54 suggest
Precursor for migration to the lymph nodes
61
Describe how the h-CLAT is carried out
Exposed to a test chemical for 24hrs Treated with fluorescent antibodies Flow cytometry

PED3011 Toxicology (11 decks)

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