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, (2002)
( nm) blocked by ozone layer Produced by some artificial light sources May penetrate top layers of skin ( nm) responsible for sunburn Contributes little to tanning Causes squamous cell carcinoma and Leathery skin ( nm) penetrates deep into the Dermis. Causes wrinkles, blotches & age-spots Stimulate melanin to tan Contributes to sunburn UVC UVB UVA 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, (2002)
ObservationResult in Phototoxicity Result in Photoallergy Reaction to first exposurePresentAbsent Latency between exposure & responseVariableMay occur Gross reactions to structurally related compounds AbsentVaried Clinical changesLike sunburnVaried Flares at previously involved sitesNeverPossible Development of persistent light reactionNeverRarely Incidence for a given compoundVery highUsually low Concentration of drug required for reactionHighLow Action spectrum & absorption spectrumNormally similarAction spectrum at longer Results of photo patchImmediateDelayed
SulfonamidesFurocoumarins Chlorodiazepoxide Methyldopa Protriptylline
NorethisteroneNalidixic acid Tetracyclines Chlorpromazine Thiazides
DoDo 1D1D 3D3D 1 O 2 + D o D o + A H D - + A H + or A-OO-H AH 3O23O2 absorption fluorescence or Internal conversion singlet excited state triplet excited state singlet oxygen intersystem crossings phosphorescence or intersystem crossings ground state absorbs light AH e - promoted to next energy level e - spin state not changed O 2 in ground state, exists as a triplet peroxy molecule Type II Type I Free radical
Proteins - amino acids eghistidine Tryptophan - types I (free radical) and types II 1 O 2 Type II reaction Imidazole ring reacts with 1 O 2 adding O 2 across the double bond, forming an unstable cyclic intermediate which subsequently breaks down Histidine in protein gets damaged +
Lipids Type II reaction 1 O 2 adds across double bond of lipid molecule Lipids are found in cell membrane, reaction leads to disruption of the cell membrane and cell death
Carbohydrates - alcohols, sugars, vitamin C 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 alcoholketone
Nucleic Acids - Purines Guanine, xanthine + 1 O 2 Purines can be oxidised and therefore are susceptible to attack by singlet oxygen. Not as susceptible as histidine or tryptophan, but damage does occur Type II damage
Drug or pollutant 1 O 2 prod. (1) Free radical generation (2) Phototoxicity in Mouse (3) Clinical Reports of Phototoxicity (4) 8-Methoxypsoralen3739strongVery many Cloropromazine5436strongmany Pomazine2017moderatefew Hydrochlorothiazide1314strongmany Frusemide4022strongmany Nalidixic acid20018strongmany Cloroquine1814weakfew Diazepam4<0.1weakfew Chlorodiazepoxide2<0.1weakfew
Qinine962weakfew Metronidazole0scavengermoderatefew Azathioprine1scavengermoderatemany Benoxaprofen3742strongVery many Naproxen1511moderatesome Indometacin<1<0.1nonefew Oxytetracycline110.5moderatesome Demeclocycline135strongmany Dimethylbenzantracene2323Strong (topical)many Benzacridine1852strongmany Comparison of fundamental photochemical activity with mouse phototoxicity tests and clinical photosensitivity responses (1) Based on O 2 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 Excited State Drug Triplet State Energy transfer to molecular O 2 Excited singlet O 2 Oxidation-peroxidation of biomolecule (lipid, protein) Energy transfer to biomolecule Oxidation of excited state biomolecule Molecular change Free Radicals Formation of photoproduct(s) Electron transfer or covalent binding to biomolecule Molecular change to cell components Photo-oxidation of cell components Toxic reaction with cell components Damage to critical cell components Phototoxic Skin Response Deactivation Mechanisms (Fluorescence, Internal conversion, etc) hh hh
Peroxy radical radical
Hydroxyl radical
carbazole photosubstitution photoreduction Secondary photoproduct
Naproxen Ketoprofen Ibuprofen Suprofen Benoxprofen Sulindac Indomethacin Diflusinal Diclofenac Piroxicam