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Skin fibroblasts from certain patients with the photosensitivity dermatitis/actinic reticuloid syndrome show enhanced sensitivity to ultraviolet radiation compared to normal fibroblasts. To probe further the link between oxidative damage and this disease, we have obtained a more extensive set of cell lines from patients with a severe form of the disease and examined their sensitivity towards oxidative stress by measuring cell survival following UVA radiation (330-450 nm) or hydrogen peroxide treatment (0.1-2.4 mM). The activation of the stress gene, heme oxygenase, has also been assessed by measuring the accumulation of mRNA after hydrogen peroxide treatment. Our studies have confirmed that a slight ultraviolet sensitivity is a characteristic of photosensitivity dermatitis/actinic reticuloid syndrome cell strains and we further demonstrate that these cell lines are particularly sensitive to hydrogen peroxide with up to a three- to fourfold increased sensitivity as compared to normal controls. We also show that certain ataxia telangiectasia strains that are especially sensitive to hydrogen peroxide are also slightly sensitive to ultraviolet radiation. Hydrogen peroxide induces accumulation of mRNA for the oxidant-inducible stress protein, heme oxygenase, with similar kinetics (maximum mRNA accumulation 2-4 h following treatment) and with a similar range of magnitudes in both normal (6.6-20.6 times mRNA increase over basal levels) and photosensitivity dermatitis/actinic reticuloid (2.9-12.8 times) skin cells. Because cells from photosensitivity dermatitis/actinic reticuloid patients show increased sensitivity towards oxidative stress but show no significant change in oxidant activation of the heme oxygenase gene, we propose that the defect involves a late stage of processing of oxidative damage rather than a compromised free radical scavenging system.

Ciprofloxacin is one of the new series of broad-spectrum antibiotic quinolones, chemically related to nalidixic acid and which may, therefore, induce photosensitization of human skin. Three in vitro tests for phototoxicity: the destruction of histidine, killing of mouse peritoneal macrophages and inhibition of PHA-stimulated DNA synthesis in human lymphocytes have demonstrated this photosensitizing potential with UVA irradiation at an order of magnitude lower than that for nalidixic acid. The Candida albicans test and photohaemolysis were negative. Controlled irradiation monochromator phototesting of 12 subjects, before, during and after taking ciprofloxacin showed subclinical photosensitivity with significantly lowered minimal 24 h erythema doses at 335 +/- 30 nm, 365 +/- 30 nm and 400 +/- 30 nm but not at 305 +/- 5 nm or above 400 +/- 30 nm.

Twenty-five patients suffering from severe polymorphic light eruption (PLE) were randomized to either photochemotherapy (PUVA) or narrow-band phototherapy (TL-01 UVB) treatment in early spring; patients receiving UVB were given placebo tablets to achieve a matching therapy procedure. During the 4 months following treatment, patient exposure to solar UVB was monitored with polysulphone badges. PLE occurrence, severity, and restriction of outdoor activity were recorded, using weekly diary-sheets. Analysis of covariance on this data, using the logarithm of UVB exposure as the explanatory variable, showed no significant differences between the treatments. TL-01 UVB is an effective alternative to PUVA in the management of PLE.

Cutaneous photosensitivity reactions are a consistent although uncommon feature of the fluoroquinolone group of antibiotics, which are related to nalidixic acid. Objective laboratory and clinical data are now routinely required by regulatory bodies for new drugs suspected of being photosensitizers, but no clear recommendations exist. A series of in vitro tests ranging in complexity revealed a UVA-dependent phototoxic potential for the fluoroquinolone norfloxacin similar to that for ciprofloxacin, and less than that of nalidixic acid. Controlled monochromator phototesting, designed to reveal the clinical characteristics, wavelength dependence and severity of cutaneous reactions in normal subjects showed both norfloxacin and ciprofloxacin to have a weak phototoxic potential which clears within 4 weeks of stopping the drug. UVA wavelengths (335 +/- 30 nm; 365 +/- 30 nm) appear most responsible for producing an asymptomatic erythema which is maximal at 24 h. The clinical study differs from those used previously in being blind, containing positive and negative controls, and phototesting after cessation of drug intake. The methodology has the anticipated limitation of failing to detect idiosyncratic photosensitivity responses.

Isolation of the furocoumarins (psoralens) bergapten, isobergapten, sphondin, isopimpinellin and pimpinellin from the Umbilliferous plant Heracleum laciniatum was carried out by column chromatography, and the structure and absorption spectra for the 5 furocoumarins isolated are described. Photoepicutaneous testing showed the strongest phototoxic effects from bergapten, marked effects from pimpinellin, weak effects from sphondin and none from the others. These in vivo findings were confirmed by the in vitro Candida test. Action spectrum studies demonstrated peak photosensitivity in the range 330-335 nm, bergapten being more than twice as phototoxic as pimpinellin.

SUMMARY A study of the abnormal sunlight response seen in nine patients taking benoxaprofen showed that the action spectrum was between 310 and 325 nm, which is similar to the drug's absorption spectrum. In vitro studies using three separate methods indicated that benoxaprofen has a powerful phototoxic action which may be directed mainly against cellular membranes.

Abnormal cutaneous photosensitivity is included among a number of more common side effects of tretinoin (Fig. 1; al l trans-ret inoic acid) (Pedace and Stoughton, 1971; Papa et al., 1975). The related synthetic retinoids, etretinate (Tigason) and isotretinoin (Roaccutane) (Fig. 1) may well produce a similar photosensitization. While photosensitivity is frequently listed as an adverse effect of isotretinoin, reports in the literature are contradictory. An increased susceptibility to sunburn reactions has been stated to occur in 5-12% of patients (Angel, 1983; Strauss et al., 1984) but the work of others has failed to detect this problem (Diffey et al., 1985). A single case report of clinical photosensitivity by McCormack and Turner (1983) described burning erythema of sun-exposed sites which was thought to be phototoxic in origin. Phototesting a group of subjects taking isotretinoin proved negative (Diffey et al., 1985). Etretinate has also been reported as causing sunburn reactions in 7-9% of patients (Grekin et al., 1984). Two early studies failed to produce evidence of an abnormal response to sunlight in subjects taking the drug (Ippen et al., 1978; Goerz and Orfanos, 1978) but case reports continue to appear in the literature (Collins et al., 1986).

Contact allergic sensitivity to allergens such as plants of the Compositae family is a feature of the chronic skin reaction seen in the photosensitivity dermatitis with actinic reticuloid syndrome. In fifty patients with this syndrome an increased incidence of contact allergic sensitivity to some common fragrance materials was demonstrated. Evidence is also presented, both by in vitro and in vivo studies, which indicates that a phototoxic mechanism is involved. The relevance of continued exposure to common allergens and their involvement in photosensitization mechanisms is discussed in an attempt to explain the state of 'persistent light reaction'.

Quindoxin (quinoxaline di-N-oxide) is a photosensitizer capable of producing photocontact dermatitis. The study of a group of seven affected subjects has provided evidence of persistent light reaction and "photoallergy", most probably to the parent substance and not to any photoproduct or contaminant. Clinical and photobiological similarities to the photosensitivity dermatitis and actinic reticuloid syndrome were demonstrated.

Quinine induced photosensitivity, an infrequently described adverse effect, is reported in four patients. The clinical presentation and distribution was that of a light exposed site eruption characterized by oedema and erythema in three patients, and by lichen planus in the fourth. Monochromator phototesting demonstrated abnormal delayed erythema responses in the UVB, UVA and visible wavebands. The clinical features suggested a phototoxic effect but laboratory studies indicated that the molecular mechanisms involved are unusual. Clinical and phototest evidence of abnormal photosensitivity persisted for some months after stopping quinine. Broad spectrum sunscreens are advised for the management of such patients and, where possible, cessation of quinine administration.

Using a standardized open photopatch test technique, the phototoxic reactions produced by bergamot oil bergapten (5-methoxypsoralen) the active component of the oil, and xanthotoxin (8-methoxypsoralen) were studied. The reaction was affected by a range of factors such as the vehicle (PMF or ethanol), the concentration of ethanol in the vehicle, the skin site, the interval between application of the psoralen and irradiation, the hydration of the skin, and the degree of natural or sun-induced pigmentation. Repeated photopatch testing at the same skin site produced an increase in sensitivity. Eye colour, natural susceptibility to suntanning, age, and sex, had no effect on the phototoxic response to psoralens.

Amiodarone-induced cutaneous photosensitivity was studied in 12 subjects treated with the drug. The action spectrum for the abnormal response to sunlight was shown to be within the range of 335-460 (+/- 30) nm. The clinical features of the photosensitivity response suggested that it was most probably a phototoxic reaction, a conclusion supported by the results of in vitro studies which indicated activity mainly against cell membranes. Of the five in vitro models used, three--namely photohaemolysis, the inhibition of DNA synthesis in PHA stimulated lymphocytes and the killing of mouse peritoneal macrophages--provided unequivocal evidence of the phototoxic potential of both amiodarone and its major metabolite, desethylamiodarone. In each model desethylamiodarone produced a greater effect by a factor of between 2 and 10. In vitro, UV-B wavelengths produced a greater effect than UVA but the difference between the effective wavelengths in vivo and in vitro might be explained by the greater absorption of the shorter wavelength UV-B in the epidermis. Zinc oxide-containing preparations appeared to be the most effective in reducing the cutaneous photosensitivity. It is suggested that the long-term cutaneous pigmentation resulting from oral amiodarone has a significant photosensitivity component.

Six subjects taking isotretinoin were studied, none of whom had clinical or phototest evidence of photosensitivity. Of nine subjects taking etretinate, one had convincing clinical photosensitivity consisting of a burning erythema on sunlight exposure. His phototesting results showed a marked abnormality from 300 +/- 5 nm to 365 +/- 30 nm which returned close to normal limits within one month of stopping therapy. Although clinically normal, another subject taking etretinate had similar phototest evidence of abnormal photosensitivity. In vitro photohaemolysis studies demonstrated that tretinoin (all-trans-retinoic acid) and isotretinoin have a potential, while etretinate has none. However, the major metabolite of etretinate (Ro 10-1670) had a phototoxic potential greater than that of tretinoin. The apparently low incidence of photosensitivity suggests that an idiosyncrasy is responsible, perhaps due to a disorder of pharmacokinetics or metabolism. Clinical cases should use appropriate photoprotection against UVB and UVA wavebands.

It is important in the technique of photopatch testing, using oil of bergamot, to have determined the concentration of the active psoralen, bergapten, so as to avoid false negative responses in the assessment of phototoxic reactions. Techniques for assessing the phototoxic components of oil of bergamot are described and quantitative analyses of bergapten, the only significant photoactive compound in the samples examined, are reported. The phototoxicity of bergapten was found to be nearly the same as that of xanthotoxin (8-MOP) in tests on human skin.

Of sixty-nine examples of the photosensitivity dermatitis and actinic reticuloid syndrome, nine were found to be allergically sensitive to chrysanthemum oleoresin extract. Although this extract showed evidence in vitro of a phototoxic action we were unable with in vivo studies to explain the connection between the contact allergic sensitivity and the photosensitivity. The fractions responsible for the in vitro phototoxicity appear to be different from those involved in the in vivo contact allergic sensitivity. This study provides further support for the view that in the photosensitivity dermatitis and actinic reticuloid syndrome contact allergic sensitivity is of importance.