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Possible augmentation of photosensitivity by dietary furanocoumarins in patients with systemic lupus erythematosus 1Faculty of Nutrition and Food Sciences, Department of Clinical Nutrition and Dietetics, Shahid Beheshti University of Medical Sciences (SBMU),Tehran, Iran; 2National Nutrition and Food Sciences Technology Research Institute, Tehran, Iran; and 3Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA that can cause photosensitization.5,11 Skin expo-sure to some FC-rich foods, such as figs, parsley, Systemic lupus erythematosus (SLE) is an autoim- celery, and parsnip, may also induce photosensitiv- mune disease with characteristic involvement of ity.12-17 The consumption of a large quantity of multiple organ systems, resulting in photosensitive celery root 1 h prior to a visit to a tanning parlor skin eruptions, arthritis, serositis, nephritis, and has been associated with generalized phototoxic hematologic abnormalities. Lupus-specific skin reactions.15,18 Increased phototoxicity is a key lesions and systemic flares of this disease can be consequence of higher blood levels of the FCs pso- triggered by excessive exposure to UVB and long- ralen, 8-methoxypsoralen (8-MOP) and 5-methox- wave UVA light. The mechanisms that underlie the ypsoralen (5-MOP), which are in turn increased photosensitivity of SLE have been postulated to after ingestion of FC-rich food items. In contrast include modulation of autoantibody location, cyto- to most other phototoxins, DNA is the major toxic effects, apoptosis induction with systemic dis- target of FC-induced photosensitive reactions.19 persal of autoantigens from apoptotic blebs, Schlatter and colleagues examined whether the upregulation of adhesion molecules and cytokines, FC content of vegetables is sufficient to induce pho- induction of nitric oxide synthase expression and totoxic skin reactions in healthy human volunteers after ultraviolet irradiation.16 The ingestion of Furanocoumarins, or FCs, are a class of organic 300 g of celery roots (total phototoxic FC content chemical compounds produced by a variety of 8.5 grams) followed by UVA exposure (1.5–9 J/ plant families (Apiaceae, Rutaceae, Fabaceae, and cm2) did not result in any skin reactions, and the Moraceae)3 and are recognized as potent phyto- blood levels of the FCs (psoralen, 8-MOP and 5- alexins and allelochemical compounds.4-6 FCs pos- MOP) remained below the analytical detection limit of 2 ng/ml. 8-MOP and 5-MOP are the two stemming in part from their planar structure, most important FCs in vegetables. When 15 mg of which allows these tricyclic molecules to intercalate each were ingested separately in a 50% alcoholic into DNA. Once intercalated, the molecule may be solution, a strong and persistent erythema was activated by UVA (320–400 nm) light, forming a induced in three out of the four subjects (UVA covalent monoadduct complex between either the dose: 3–25 J/cm2). The blood levels immediately 40,50 furan or the 3,4 pyrone side of the FC, and the before UVA irradiation ranged from 14–114 ng/ 5,6 double bond of a pyrimidine base, most fre- ml for 8-MOP, and 17–70 ng/ml for 5-MOP. The quently thymidine.9 FCs can also induce the forma- blood levels remained at trace levels (3 ng/ml) in the tion of reactive oxyradicals and free radicals that one subject who did not show phototoxicity. Two can damage biologically sensitive molecules.10 subjects in the study of Schlatter et al. were also Celery, parsley, and parsnips contain linear FC tested with a mixture of 10 mg 8-MOP plus 10 mg phytoalexins (psoralen, bergapten, and xanthotoxin) 5-MOP. In one subject the mixture induced pig-mentation only, while in the other it induced Correspondence to: Reza Rastmanesh, PhD, Faculty of Nutrition and mild-to-medium erythema. The blood levels of the Food Sciences, Department of Clinical Nutrition and Dietetics, Shahid FCs in the two subjects were similar (12–15 ng/ml Beheshti University of Medical Sciences (SBMU), Tehran, Iran for 8-MOP and 5-MOP).16 These experiments indi- Email: [email protected] 28 March 2011; accepted 24 May 2011 cated that the phototoxic threshold dose of FC ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav mixtures is of the order of 10 mg 8-MOP plus 10 mg Ultraviolet radiation can induce skin lesions and 5-MOP in humans. Since a normal dietary portion systemic disease flares in patients with SLE, and of celery roots is approximately 100–150 grams, the both UVA and UVB light can induce phototoxic expected dietary intake of phototoxic FCs would be reactions in these patients.34 SLE patients have a approximately 3–4 mg. However, actual dietary significantly reduced MED to UVB irradiation intake could be substantially higher as a result of compared with healthy persons.35 Thus, normal dietary fads or other unusual dietary habits. Thus, or excessive dietary intake of FCs has the potential the safety factor between the actual amount of die- tary FC ingestion and phototoxic doses may be a Furthermore, renal insufficiency is very common in patients with SLE,36-38 and could augment the Intra-individual differences in the oral bioavailabil- phototoxic effects of the FC’s as a result of lower ity, kinetics, and hepatic metabolism of FCs are well FC clearance and excretion. Photoadducts of DNA documented, and would be expected to lead to vari- and 8-MOP have been found to cross-react with able blood levels following ingestion of a defined naturally occurring human anti-DNA autoantibo- amount of FCs and thus a variable potential for pho- dies, providing an additional mechanism for the tosensitization.20-24 This may explain the variable induction of an SLE flare following increased FC blood levels in the experimental subjects of Schlatter et al. after the same dose of FCs. The absorption of The potential for FC-rich diets to enhance pho- FCs is also influenced by diet,25-27 quantity of food tosensitivity in patients with SLE has not been eaten,28 and medications.29 For example, it is known examined. There are scant data in the literature that the oral bioavailability and pharmacokinetics of regarding FC intake in SLE patients, and the rela- the FCs in celery root are different when ingested as a tion of a high-FC diet to photosensitization is less well documented. However, our dietitian colleagues Cutaneous photosensitive reactions induced by in Iran have reported anecdotally that many exogenous agents are classified as either phototoxic patients with SLE recall the ingestion of large or photoallergic on the basis of certain key distin- amounts of FC-rich food items, such as celery or guishing features. Phototoxic eruptions have a rela- grapefruit juice, hours or days before the develop- tively high incidence, occur in sun-exposed skin only, ment of photosensitive reactions, although precise follow exposure to large amounts of the exogenous figures are hard to establish. There are two agent, and develop within minutes to hours after case reports of patients developing systemic and exposure to the photosensitizer and light. In contrast, discoid lupus erythematosus in the context of photoallergic reactions are rare, may spread from psoralen plus long-wave ultraviolet (PUVA) ther- sun-exposed to unexposed skin, follow exposure to apy.40,41 However, antinuclear antibodies were not small amounts of the photosensitizing agent, require induced in a prospective study of PUVA therapy an initial sensitization period, and develop at least 24 h after exposure to the drug and light.30 The FCs Dietary FC intake is common to all demographic are unusual in that they induce delayed phototoxic strata. It is greatest in late adolescence and early reactions which peak 36–72 h after UVA exposure.
adulthood when carbonated beverages are con- Cutaneous sensitization to UVB light by exogenous sumed heavily.43 Non-white races seem to have agents is measured 24 h after light exposure and higher dietary exposure. Dietary FC intake is a quantified as the minimal erythema dose (MED). In function of dietary patterns inherent to different contrast, UVA light photosensitization is assessed individuals and to their countries of origin. It also after 48–96 h and is quantified as the minimal photo- depends on the freshness of the vegetables. Light toxic dose. Both measures are influenced by a variety and temperature changes and contamination by of factors, including skin pigmentation, pigment fungi and other microbes may increase FC content adaptation, skin thickness, the presence and thick- during vegetable storage.6,44-46 Dermal exposure to ness of hair, age, diet, and body site.31 FC-containing plants is another source of FCintake.47 Western diet is in the range of 548 and 2237 mg/ Dietary furanocoumarins and photosensitivity day for the average and high consumer, respec- tively.48 Grapefruit juice, but not citrus-flavorednon-alcoholic beverages, appears to be the major Photosensitivity is a characteristic of patients with source of FC exposure in a Western diet.48 There SLE,1,32 being reported in up to 73% of patients.33 may be important variations in dietary FC intake Dietary FCs in patients with SLER Rastmanesh and AN Baer between countries and within individuals. For The interviewer showed the photographs of the example, some obese people in countries such as standard serving size, and asked the subjects to Iran habitually drink up to 300 ml of celery juice refer to those portions when selecting the amount daily, presumably to lose weight. This corresponds to an estimated FC content of 28–100 mg/g,15,16which equates to a total of 8.4–30 mg. Thus, if thephototoxic threshold dose of FC mixtures is of the order of 10 mg 8-MOP plus 10 mg 5-MOP (yielding8-MOP and 5-MOP blood levels 30 min after inges- It is possible to reduce an individual’s intake of tion of about 10–15 ng/ml each),16 it would be some FCs with food processing techniques. For highly possible that even a single dose of 300 ml example, heat treatment of grapefruit juice reduces celery juice (yielding 28–100 mg/g FC) might be the concentrations of FCs such as bergamottin and capable of inducing or aggravating photosensitivity 6’,7’-dihydroxybergamottin.49 However, cooking procedures (boiling or microwaving) are not effec- There are other dietary habits which might sig- tive in destroying the psoralen content of pars- nificantly enhance the total amount of FCs. In Iran, nips.50 Also, handling and storage conditions these include the ingestion of 3–4 figs per day to influence FC contents.45,51 Storage of whole pars- avoid or ameliorate constipation, the addition of nips, but not of cubes or homogenate, at 4C 1–2 tablespoons of lime juice to water and tea on resulted in a marked biphasic increase of FC con- hot days, the ingestion of celery casserole in centrations after 7 and 38 days of storage, up to summer, and the imbibing of caraway or cumin levels of about 40 mg/kg (from initial levels lower elixir. Table 1 lists some, but not all of, the dietary than lower than 2.5 mg/kg).45 FCs are more con- items that contribute to FC intake in an Iranian centrated in the fruit and vegetable skin and, there- population. The data are derived from a study of fore, peeling FC-rich fruits, when possible, may be 75 patients with rheumatoid arthritis. The nutrient useful.18,50,51 It is possible to remove FCs from intake of the subjects was estimated with inter- grapefruit juice with the addition of certain edible viewer-administered semi-quantitative food fre- quency questionnaires that included a list of 66food items. Selection criteria were food items con-sumed most frequently, those consumed in greatestamounts, and those supplying each nutrient, especially antioxidant vitamins as well as FCs.
Subjects were asked to state the average frequency Ethical concerns would preclude direct study of the of consumption of each food item according to the effect of exogenously administered psoralens on the categories of frequency, none to three times a day.
phototoxic threshold in SLE subjects, since these Average of furanocoumarin intake in Iranian patients with rheumatoid arthritis *It is quite common to squeeze up to 10 celery roots to get 300 ml celery juice. Celery roots that are not fresh may have higherfuranocoumarin (FC) content. Light and temperature changes, microbial and fungal infection, and contaminations mayincrease FC content during storage.6,44-46 Thus, in some occasions FC intake can be much higher. Total FC intake maythus be far greater than the 10–15 mg FC doses that proved phototoxic. There are several other food items that contain FCs.
These have not been included in the table, since there is no established analytical method to determine their preciseconcentration.
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