Transcript Photodynamic Action

Action spectrum (approximate) for the induction of erythema in human skin, and average
intensity at the earth’s surface. The figure also depicts the ranges of various UV regions.
D. E. Moore, Drug Safety, 25, 345-372 (2002)
UVC (200-280nm) blocked by
ozone layer
Produced by some
artificial light sources
May penetrate top layers
of skin
UVB (280-320nm) responsible
for sunburn
Contributes little to
tanning
Causes squamous cell
carcinoma and
Leathery skin
200
250
300
UVA (320-400nm) penetrates
deep into the
Dermis.
Causes wrinkles,
blotches & age-spots
Stimulate melanin to tan
Contributes to sunburn
http://medlib.med.utah.edu/kw/derm/pages/meet_2.htm accessed 16/7/06
Absorption spectra of DNA (calf thymus) and protein (bovine
serum albumin at equal concentrations (20 µg/ml).
D. E. Moore, Drug Safety, 25, 345-372 (2002)
D. E. Moore, Drug Safety, 25, 345-372 (2002)
Observation
Result in
Phototoxicity
Result in
Photoallergy
Reaction to first exposure
Present
Absent
Latency between exposure & response
Variable
May occur
Gross reactions to structurally related
compounds
Absent
Varied
Clinical changes
Like sunburn
Varied
Flares at previously involved sites
Never
Possible
Development of persistent light reaction
Never
Rarely
Incidence for a given compound
Very high
Usually low
Concentration of drug required for reaction
High
Low
Action spectrum & absorption spectrum
Normally similar
Action spectrum
at longer
Results of photo patch
Immediate
Delayed
Sulfonamides
Furocoumarins
Protriptylline
Methyldopa
Chlorodiazepoxide
Norethisterone
Nalidixic acid
Tetracyclines
Chlorpromazine
Thiazides
Do
ground state
absorbs light
absorption
fluorescence or
Internal conversion
1D singlet excited state
-
e promoted to next energy level
e- spin state not changed
intersystem crossings
phosphorescence
or intersystem crossings
3D triplet excited state
AH
3O
2
O2 in ground state,
exists as a triplet
1O
Free radical
Do + A• H•
or
Type I D- + A• H+
2 + Do
singlet oxygen
AH
A-OO-H
peroxy molecule
Type II
Proteins - amino acids eghistidine
+
Type II reaction
Imidazole ring reacts with 1O2 adding O2 across the double
bond, forming an unstable cyclic intermediate which
subsequently breaks down
Histidine in protein gets damaged
Tryptophan - types I (free radical) and types II 1O2
Lipids
Type II reaction
1O adds across double bond of lipid molecule
2
Lipids are found in cell membrane, reaction leads
to disruption of the cell membrane and cell death
Carbohydrates - alcohols, sugars, vitamin C
alcohol
ketone
Type I reaction
Contain many hydroxyls (-OH) which interact with the triplet
excited state giving a free radical reaction
A free radical is formed and can react further
Nucleic Acids - Purines
Guanine, xanthine + 1O2
Type II damage
Purines can be oxidised and therefore are susceptible to
attack by singlet oxygen.
Not as susceptible as histidine or tryptophan, but
damage does occur
Drug or pollutant
1O
2prod.
(1)
Free radical
generation
(2)
Phototoxicity Clinical
in Mouse (3)
Reports of
Phototoxicity
(4)
8-Methoxypsoralen
37
39
strong
Very many
Cloropromazine
54
36
strong
many
Pomazine
20
17
moderate
few
Hydrochlorothiazide
13
14
strong
many
Frusemide
40
22
strong
many
Nalidixic acid
200
18
strong
many
Cloroquine
18
14
weak
few
Diazepam
4
<0.1
weak
few
Chlorodiazepoxide
2
<0.1
weak
few
Qinine
96
2
weak
few
Metronidazole
0
scavenger
moderate
few
Azathioprine
1
scavenger
moderate
many
Benoxaprofen
37
42
strong
Very many
Naproxen
15
11
moderate
some
Indometacin
<1
<0.1
none
few
Oxytetracycline
11
0.5
moderate
some
Demeclocycline
13
5
strong
many
Dimethylbenzantracene
232
3
Strong (topical)
many
Benzacridine
185
2
strong
many
Comparison of fundamental photochemical activity with mouse phototoxicity
tests and clinical photosensitivity responses
(1) Based on O2 uptake and flash photolysis measurements. (2) Based on
polymerisation and electron spin resonance experiments. (3) Adapted from
various literature reports (4) Adapted from ADRAC and Magnus
Photsensitising Drug
h
Deactivation Mechanisms
(Fluorescence, Internal conversion, etc)
Excited State Drug
Triplet State
Energy transfer
to molecular O2
Free Radicals
Energy transfer
to biomolecule
Electron transfer or
covalent binding to
biomolecule
Formation of
photoproduct(s)
h
Excited singlet O2
Oxidation-peroxidation
of biomolecule (lipid,
protein)
Oxidation of excited
state biomolecule
Molecular change to
cell components
Photo-oxidation
of cell
components
Molecular change
Toxic reaction with
cell components
Damage to critical cell components
Phototoxic Skin Response
radical
Peroxy radical
radical
Hydroxyl radical
carbazole
photosubstitution
photoreduction
Secondary photoproduct
Naproxen
Suprofen
Sulindac
Diclofenac
Ketoprofen
Ibuprofen
Benoxprofen
Indomethacin
Diflusinal
Piroxicam