Drug-induced photosensitivity: phototoxic and photoallergic reactions--a few molecular aspects

Drug-induced photosensitivity involves mainly phototoxic and photoallergic reactions. The main features of phototoxic and photoallergic reactions are presented and some molecular aspects involved in the mechanisms leading to an adverse skin response are illustrated with examples.     

Evidence for a photoprotective function of low-temperature-induced anthocyanin accumulation in apple and pear peel

The light requirement and low-temperature stimulation of anthocyanin synthesis in peel of apple ( Malus domestica ) and pears ( Pyrus communis ) and the presence of anthocyanins in immature fruits are not congruent with a visual function in dispersal. We hypothesized that anthocyanins afford photoprotection to peel during low-temperature-induced light stress and that the protection is not a fortuitous side-effect of light absorption by anthocyanin. The extent of photoinhibition at harvest and after light stress treatment in pear cultivars differing in redness decreased with increasing red color on the sun-exposed sides of fruits. Green-shaded sides of the pears showed comparable levels of photoinhibition indicating that pears did not differ in their inherent photosensitivity. Apple and pear peel show considerable short-term fluctuation in redness in response to temperature, with red color increasing rapidly in response to low temperature and just as quickly fading in response to high temperature. Briefly, shading pears and apples during cold conditions for 2 days reduced the accumulation of anthocyanin and increased the photosensitivity of peel. Subsequent shading during warm conditions did not affect the accumulation of anthocyanin or the photosensitivity of peel indicating that the response at low temperature was not due to shade adaptation. The assessment of photosystem II (PSII) efficiency and quenching of chlorophyll fluorescence between 16 and 40°C indicated that 'Forelle' pear peel was particularly sensitive to photostress at low temperature. The photosynthetic system in mature 'Forelle' leaves was comparatively much less sensitive to light stress at low temperature. Results support the view that anthocyanins are adaptable light screens deployed to modulate light absorption in sensitive tissues such as fruit peel in response to environmental triggers such as cold front snaps.     

Spectral sensitivity in a sponge larva

Cilia at the posterior pole of demosponge larvae are known to cause directional swimming, sometimes in response to light gradients, but so far neither the spectral sensitivity of, nor the molecular basis for, this response has been investigated. We exploited the fact that the larval cilia respond to sudden changes in light intensity, a shadow response, in order to determine the action spectrum of photosensitivity. Our results show that larvae of the haplosclerid sponge Reniera sp. respond most to blue light (440 nm), and have a smaller, secondary response peak to orange-red light (600 nm). These data suggest that the photoreceptive pigment in sponge larvae may be a flavin or carotenoid.     

Nuclear Suppressors of the Photosensitivity Associated with Defective Photosynthesis in Chlamydomonas reinhardii

Several nuclear mutations were recovered that suppress the photosensitivity associated with the Chamydomonas reinhardii chloroplast mutant rcl-u-1-10-6C, which is defective in ribulose-1,5-bisphosphate carboxylase/oxygenase. Two of the suppressor mutations affect other components of photosynthesis. These results show that suppressors of photosensitivity are sufficiently common to permit the recovery of photosensitive, photosynthesis-deficient mutants in bright light, and indicate that photosynthesis-deficient mutants selected and maintained in the light may accumulate suppressors which can confuse the biochemical analysis of lesions in photosynthesis. One of the suppressor mutations inhibits photosystem II activity, indicating that photosensitivity can be mediated by partial reactions of the photosynthetic electron transport chain.     

系统性光变态反应检测动物模型的建立

目的建立稳定、完善的系统性光变态反应检测的动物模型。方法以对氨基苯磺酰胺（SN）作为光敏剂,经腹腔注射与灌胃两种途径对小鼠和豚鼠进行给药,通过UVA加UVB光照诱导以及只用UVA光照激发后,于4h、24h、48h和72h分别测量小鼠耳厚度及观察豚鼠皮肤红斑反应。结果24h、48h和72h时,小鼠出现耳肿胀反应,豚鼠出现皮肤红斑反应。结论口服、腹腔注射SN,均可产生光变态反应,成功建立系统性光变态反应检测的动物模型。     

棉铃虫蛾复眼光反应特性

用视网膜电位图(electroretinogram,ERG)技术研究了棉铃虫Helicoverpa armigera蛾暗适应过程中对单色光和白光刺激的光感受性变化。结果显示：(1)依ERG振幅大小(峰-峰值),在340～605 nm波谱内有3个大小不等的峰-主峰位于绿 黄光区562 nm,次峰在蓝光区483 nm,第3个峰在近紫外区400 nm,显示其至少有3种感受器;(2)性别、日龄及暗适应时间长短对其光谱敏感性有影响,低龄时雄蛾对单色光刺激较雌蛾敏感,高日龄时相反;1～5日龄内, 3日龄蛾的视网膜电位(ERP)值最高;随暗适应时间延长,其复眼对近紫外区400 nm敏感性明显增加;(3)一定光强度范围内,随单色光和白光光强度增强该蛾复眼的ERP值增大,初期增加较缓,中期较快,呈近似S型曲线,显示其复眼具有较强的光强度自调节和适应机制。     

Phosphorylated Thiamine Derivatives and Cortical Activity in the Baboon Papio papio: Effect of Intermittent Light Stimulation

The effect of intermittent light stimulation (ILS) on the distribution of thiamine derivatives in three brain areas (occipital, motor, and premotor) was compared in photosensitive and nonphotosensitive baboons. ILS induces paroxysmal discharges in the motor and premotor areas of photosensitive animals only. In baboons submitted to ILS, thiamine triphosphate (TTP) decreases in both photosensitive and nonphotosensitive animals; thiamine monophosphate (TMP) increases in photosensitive animals, which present ILS-induced paroxysmal discharges, whereas it is unaffected in nonphotosensitive animals. The variations are the most significant in the occipital (visual) cortex. A consumption of TTP may result from electrical activity induced by light stimulation in the occipital area. No correlation between ILS-induced paroxysmal activity and a decrease in TTP contents was found. However, photosensitive animals are affected differently from nonphotosensitive animals, as their content of TMP in the cerebral cortex increases on stimulation. However, as long as the exact role of thiamine compounds in relation to membrane excitability in the nervous system remains unknown, it is impossible to conclude whether the differences observed in the metabolism of thiamine compounds are the cause or the consequence of the photosensitivity in the baboon Papio papio.     

Reflection versus fluorescence: a note on the physical backgrounds of two types of light microscopy.

Bright microscopic images against a dark background can be originating not only from fluorescence, but also from selective reflection. Selective reflection or scattering of visible light in microscopic preparations can be used for the visualization of sometimes otherwise barely distinguishable material. The images obtained superficially resemble those from fluorescence microscopy. They do not, however, result from huminescence but from selectively reflected light with wavelengths in the region of the absorbance peak of the chromophore present in the stained biological material. The respective backgrounds of the underlying physical phenomena and the conditions under which selective reflection can occur are discussed.     

Santalbic acid in the plant kingdom

The occurrence and distribution of santalbic acid in the plant kingdom are reported and discussed. This conjugated acetylenic fatty acid, octadeca-11-trans-en-9-ynoic acid (in “Delta Notation” 18:2Δ9a,11t), occurs in members of the santalalean plant families, mostly in tropical and subtropical areas. The range is from only traces up to 95.0?% of total fatty acids in the seed oil. However, some caution is required during the analysis, so the presence of this acid may have been overlooked sometimes. This fatty acid may be toxic to humans, but may be of interest for technical purposes because of a reactive functional group.     

Expression of Advanced Glycation End-Products on Sun-Exposed and Non-Exposed Cutaneous Sites during the Ageing Process in Humans

The glycation process is involved in both the intrinsic (individual, genetic) and extrinsic (ultraviolet light, polution and lifestyle) aging processes, and can be quantified at the epidermal or dermal level by histological, immunohistochemical (IHC), or imagistic methods. Our study is focused on a histological and immunohistological comparison of sun-protected regions versus sun-exposed regions from different age groups of skin phototype III subjects, related to the aging process. Skin samples collected from non-protected and UV protected regions of four experimental groups with different ages, were studied using histology and IHC methods for AGE-CML [N(epsilon)-(carboxymethyl)lysine]. A semi-quantitative assessment of the CML expression in the microvascular endothelium and dermal fibroblasts was performed. The Pearson one-way ANOVA was used to compare data between the groups. In the dermis of sun-exposed skin, the number and the intensity of CML positive cells in both fibroblasts and endothelial cells (p<0.05) was higher compared to sun-protected skin, and was significantly increased in older patients. The sun-exposed areas had a more than 10% higher AGE-CML score than the protected areas. No statistically significant correlation was observed between the histological score and the IHC expression of CML. We concluded that in healthy integument, the accumulation of final glycation products increases with age and is amplified by ultraviolet exposure. The study provides new knowledge on differences of AGE-CML between age groups and protected and unprotected areas and emphasizes that endothelium and perivascular area are most affected, justifying combined topical and systemic therapies.     

Photosensitivity in Smith-Lemli-Opitz syndrome: a flux balance analysis of altered metabolism

Ultraviolet A photosensitivity is a debilitating symptom associated with the metabolic disorder Smith-Lemli-Opitz syndrome (SLOS). SLOS is a manifestation of the deficiency of 7-dehydrocholesterol reductase, an enzyme involved in the cholesterol biosynthesis. As a result several abnormal intermediary compounds are formed among which Cholesta 5, 7, 9(11)-trien-3beta-ol is the most likely cause of photosensitivity. The effect of various drugs acting on cholesterol biosynthetic pathway on SLOS is not clear as clinical trials are not available for this rare disorder. A Flux Balance Analysis (FBA) has been carried out using the software CellNetAnalyzer or FluxAnalyzer to gain insight into the probable effects of various drugs acting on cholesterol biosynthetic pathway on photosensitivity in SLOS. The model consisted of 44 metabolites and 40 reactions. The formation flux of Cholesta 5, 7, 9(11)-trien-3beta-ol increased in SLOS and remained unchanged on simulation of the effect of miconazole and SR31747. However zaragozic acid can potentially reduce the flux through the entire pathway. FBA predicts zaragozic acid along with cholesterol supplementation as an effective treatment for photosensitivity in SLOS.     

The distribution and diel vertical migration of Pseudodiaptomus hessei (Mrázek) (Calanoida: Copepoda) in a subtropical lake in southern Africa

The vertical distribution and diel migratory behaviour of Pseudodiaptomus hessei in a freshwater lake is described. All stages showed a pronounced diel migration. During daylight naupliar and copepodite instars were almost exclusively benthic in shallow areas (<10m). Copepodite V and adult stages were predominantly benthic even at 40 m. The diurnal vertical distribution pattern implies age-related differences in photosensitivity and a possible depth-regulatory mechanism, based on the existence of differential photosensitivity, is offered to account for day-depth control. Nocturnal vertical distribution, studied approximately fortnightly during 1970–71, showed no clear seasonal variation. Variations in pattern, most obvious in adult instars, correlated with prevalent lunar conditions. Nocturnal or midnight sinking was evident, particularly in post-naupliar stages. Dusk rise and dawn descent were performed at very low light intensities and paralleled changes in light penetration. Dawn descent was less rapid than the dusk rise. An ephemeral dawn rise was sometimes observed but was not a consistent feature of all stages. An endogenous rhythm of locomotor activity was recorded under laboratory conditions. Activity was low during daylight, increased sharply at dusk and then decreased through the night to reach daytime levels at dawn. The stimulus provided by changes in light intensity and/or endogenous activity changes can account for the dusk and dawn movements of P. hessei but a definitive identification of the direct migratory stimulus is not possible. Attention is called to a closer examination of the role of endogenous activity rhythms in vertical migratory behaviour. The possible adaptive value of vertical migration to P. hessei is examined briefly.     

Jacobsen syndrome

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients.     

WHALE REACTIONS TO HUMAN ACTIVITIES IN CAPE COD WATERS

A review of our whale observations of more than 25 years indicated that each of the species commonly observed within 35 km of Cape Cod reacted differently to stimuli from human activities, and that these responses have gradually changed with time. Over the years of exposure to ships, for example, minke whales ( Balaenoptera acutorostrata ) have changed from frequent positive interest to generally uninterested reactions, finback whales ( B. physalus ) have changed from mostly negative to uninterested reactions, right whales ( Eubalaena glacialis ) have apparently continued the same variety of responses with little change, and humpbacks ( Megaptera novaeangliae ) have dramatically changed from mixed responses that were often negative to often strongly positive reactions. These reactions appeared to result mostly from three types of stimuli: primarily underwater sound, then light reflectivity, and tactile sensation. The whale reactions were related to their assessment of the stimuli as attractive, uninteresting or disturbing, their assessment of the movements of the sources of the stimuli relative to their own positions, and their assessment of the occurrence of stimuli as expected or unexpected. Whale reactions were modified by their previous experience and current activity: habituation often occurred rapidly, attention to other stimuli or preoccupation with other activities sometimes overcame their interest or wariness of stimuli, and inactivity seemed to allow whales to notice and react to stimuli that otherwise might have been ignored. The changes over time in the reactions of whales to stimuli from human activities were gradual and constantly varying with increased exposure to these activities.     

Reflection versus fluorescence

Summary Bright microscopic images against a dark background can be originating not only from fluorescence, but also from selective reflection. Selective reflection or scattering of visible light in microscopic preparations can be used for the visualization of sometimes otherwise barely distinguishable material. The images obtained superficially resemble those from fluorescence microscopy. They do not, howeverm result from luminescence but from selectively reflected light with wavelengths in the region of the absorbance peak of the chromophore present in the stained biological material. The respective backgrounds of the underlying physical phenomena and the conditions under which selective reflection can occur are discussed.     

Red 'Anjou' pear has a higher photoprotective capacity than green 'Anjou'

Photoprotective function of anthocyanins along with xanthophyll cycle and antioxidant system in fruit peel was investigated in red 'Anjou' vs green 'Anjou' pear (Pyrus communis) during fruit development and in response to short-term exposure to high light. The sun-exposed peel of red 'Anjou' had higher maximum quantum yield of photosystem II (F(V)/F(M)) than that of green 'Anjou' and both the sun-exposed peel and the shaded peel of red 'Anjou' had smaller decreases in F(V)/F(M) after 2-h high light (photon flux density of 1500 mumol m(-2) s(-1)) treatment than those of green 'Anjou'. At the middle and late developmental stages, the xanthophyll cycle pool size on a chlorophyll basis, the activity of superoxide dismutase, ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), dehydroascorbate reductase (DHAR) and glutathione reductase (GR) and the level of reduced ascorbate and total ascorbate pool in the sun-exposed peel were either the same or lower in red 'Anjou' than in green 'Anjou', whereas the xanthophyll cycle pool size on a chlorophyll basis and the activity of APX, catalase, MDAR, DHAR and GR in the shaded peel were higher in red 'Anjou' than in green 'Anjou'. It is concluded that red 'Anjou' has a higher photoprotective capacity in both the sun-exposed peel and the shaded peel than green 'Anjou'. While the higher anthocyanin concentration along with the larger xanthophyll cycle pool size and the higher activity of some antioxidant enzymes may collectively contribute to the higher photoprotective capacity in the shaded peel of red 'Anjou', the higher photoprotective capacity in the sun-exposed peel of red 'Anjou' is mainly attributed to its higher anthocyanin concentration.     

Phase I xenobiotic metabolic systems in plants

Phytoremediation uses living higher plants for the removal and biochemical decomposition of environmental pollutants. In this paper Phase I metabolic pathways in the biotransformation reactions of organic pollutants in plants are reviewed. These reactions result in the introduction of functional groups in the xenobiotic molecule or the exposure of preexisting functional groups and lead to the formation of more polar, more water-soluble, chemically more reactive and sometimes biologically more active derivatives. Phase I type reactions are most important in the phytoremediation of hydrophobic, chemically stable organic pollutants, such as polycyclic aromatic hydrocarbons and (poly)chlorinated aliphatic and aromatic hydrocarbons. Although Phase I reactions involve a wide range of chemical transformations from hydrolysis to reduction, oxidative processes catalyzed by cytochrome P450 containing monooxygenases are the most important. Transgenic plants with tailored Phase I enzymatic activities may play major roles in the removal of environmentally stable organic pollutants from contaminated fields.     

The contribution of a sensitizing pigment to the photosensitivity spectra of fly rhodopsin and metarhodopsin.

Most of the photoreceptors of the fly compound eye have high sensitivity in the ultraviolet (UV) as well as in the visible spectral range. This UV sensitivity arises from a photostable pigment that acts as a sensitizer for rhodopsin. Because the sensitizing pigment cannot be bleached, the classical determination of the photosensitivity spectrum from measurements of the difference spectrum of the pigment cannot be applied. We therefore used a new method to determine the photosensitivity spectra of rhodopsin and metarhodopsin in the UV spectral range. The method is based on the fact that the invertebrate visual pigment is a bistable one, in which rhodopsin and metarhodopsin are photointerconvertible. The pigment changes were measured by a fast electrical potential, called the M potential, which arises from activation of metarhodopsin. We first established the use of the M potential as a reliable measure of the visual pigment changes in the fly. We then calculated the photosensitivity spectrum of rhodopsin and metarhodopsin by using two kinds of experimentally measured spectra: the relaxation and the photoequilibrium spectra. The relaxation spectrum represents the wavelength dependence of the rate of approach of the pigment molecules to photoequilibrium. This spectrum is the weighted sum of the photosensitivity spectra of rhodopsin and metarhodopsin. The photoequilibrium spectrum measures the fraction of metarhodopsin (or rhodopsin) in photoequilibrium which is reached in the steady state for application of various wavelengths of light. By using this method we found that, although the photosensitivity spectra of rhodopsin and metarhodopsin are very different in the visible, they show strict coincidence in the UV region. This observation indicates that the photostable pigment acts as a sensitizer for both rhodopsin as well as metarhodopsin.     

Restoration of Natural and Semi-Natural Wetland Systems in Central Europe: Progress and Predictability of Developments

After almost 40 years of experience in wetland restoration in Central Europe in which vegetation changes have been monitored by means of permanent plots or vegetation maps, some light can be shed on the intrinsic dynamics of such ecosystems, showing the limits of restoration and constraints in its manipulation. Sometimes such constraints in the restoration process can be identified, mostly being constraints in nutrient availability or in the water regime, but unexpected changes can also be the result of intrinsic species fluctuations or invasive species. Unexpected vegetation developments are sometimes undesired, can be very persistent and may indicate that environmental conditions are not suitable for target communities. Unexpected developments also illustrate the limits in restoration ecology. Very often the restoration process simply proceeds along successional pathways we did not anticipate. Theories about such alternative pathways can be explored using prediction models, such as cellular automata, which can handle the results of biomonitoring very efficiently. Biomonitoring during 40 years, however, has also shown that a certain amount of unpredictability has to be taken for granted, both in natural wetlands and in areas under restoration.