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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
Q

What is a finite dose

A

Simulation of real life exposure
Chemical that gets inside is limited by how much goes intro skin
Absorption rate changes constantly

26
Q

How can absorption be limited in a finite dose experiment

A

By dose
By vehicle ( no vehicle = no conc gradient)

27
Q

What kind of exposure times are used in a finite dose

A

6-10hr to mimic a working day
Up to 18hr for a leave on products
Wash off products 2mins - 30 days (hair dyes)

28
Q

Describe an infinite dose

A

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
Q

When can flux, lag time and permeability coefficient be measured

A

Infinite doses
The conc applied stays relatively constant w time

30
Q

Describe the metabolism of xenobiotics in the skin

A

Chemical ———-> activated chemical ———> elimination
I
I
Binding to macromolecules
I
I
Toxicity

31
Q

Where are CYP450s located in the skin

A

Basal keratinocytes and hair follicles

32
Q

Describe the role of CYP450s in the skin

A

Present at low activates when expressed
-> little effect on absorption but can cause toxicity

33
Q

What CYP450 is more expressed in the skin than the liver

A

2S1

34
Q

Describe esterases in the skin

A

Cytosolic and microsomal
Present in epidermis and dermis

35
Q

How do esterases affect drug metabolism in the skin

A

Influence absorption by reducing lipophilicity
Exploited for transdermal deliver of ester pro-drugs

36
Q

Describe alcohol and aldehyde dehydrogenase

A

Cytosolic and mitochondrial
May influence toxicity

37
Q

Describe transferases in the skin

A

Detoxify and have higher activity than P450s
Affect availability, not percutaneous absorption

38
Q

Describe NAD(P)H quinone reductases in the skin

A

Activity similar to liver
Detoxify quinines
Prevent oxidative stress

39
Q

What are examples of local topical toxicity

A

Corrosion
Contact urticarial
Physical dermatitis
Irritation
Immune reactions

40
Q

How is systemic and dermal toxicity linked

A

Dermal absorption can lead to systemic toxicity
Skin toxicity derived from systemically delivered drug

41
Q

Describe contact dermatitis

A

Erythema, scaling and thickening
Many possible causative routes by many agents

42
Q

What are the different causative routes that could lead to contact dermatitis

A

Direct damage to cells = release of cytokines
Local inflammation
Can be delayed or immediate
Doesn’t require previous exposure

43
Q

What is the proposed mechanism of action based on surfactants that lead to contact dermatitis

A

Stimulate IL-1a release = stimulate release of IL6 and IL8, phospholipase-a2 and TNFa
-> lead to cellular changes = symptoms

44
Q

What is the proposed mechanism of action that membrane damaging irritants appear to work in contact dermatitis

A

Do not appear to work solely via the release of IL-1a
Potentially operate through a ROS mechanism

45
Q

Describe allergic contact dermatitis

A

IgE mediated, phase 2 response

46
Q

Describe the induction phase of allergic contact dermatitis

A

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
Q

Describe the elicitation phase in allergic contact dermatitis

A

Allergen reacts with circulating sensitised T-lymphocyte when allergen enters viable dermatitis

48
Q

What is the difference between a hapten, prohapten and prehapten

A

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
Q

Name a few tests for skin sensitisers

A

Murine local lymph node assay
Peptide reactivity
Activation of keratinocytes and dendritic cells

50
Q

Describe the murine local lymph node assay

A

In vivo method
Measures the sensitisation phase
No longer permissible for new cosmetics

51
Q

Describe the direct peptide reactivity assay

A

‘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
Q

Why are prohaptens difficult to detect

A

No cells = no enzymes to activate prohapens -> hapten

Pretreatment with peroxidases has been proposed - could overestimate the detection of prohaptens

53
Q

Describe the role of Keap1 and Nrf2 in the cell

A

Absence of chemicals SH groups on Nrf2keap remain as SH
If Nrf2 detaches from Keap1 it is ubiquinated

54
Q

Describe the role of Keap1 and Nrf2 in the cell when there are electrophiles or ROS present

A

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
Q

Describe the KeratinoSens assay

A

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
Q

What does a positive result look like in the KeratinoSens assay

A

If ROS or electrophile present Nrf2 binds to ARE
= txn of luciferase gene
When ATP and luciferen present = visible light measures in luminometer

57
Q

Describe the KeratinoSens Assay

A

Metabolically competent
Some evidence that it can detect prohaptens

Not as good as skin S9 fraction

58
Q

Describe the h-CLAT assay

A

Monitors expression of CD86 and CD54 on the surface of THP-1 cells
Assessment of skin sensitisation potential of chemicals

59
Q

What is CD86 expression a marker of

A

Allergens

60
Q

What does the expression of the marker proteins CD86 and CD54 suggest

A

Precursor for migration to the lymph nodes

61
Q

Describe how the h-CLAT is carried out

A

Exposed to a test chemical for 24hrs
Treated with fluorescent antibodies
Flow cytometry

PED3011 Toxicology (11 decks)

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