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Home , Ammi majus, Bergapten, Heracleum sphondylium, Imperatorin, Peucedanum, Peucedanum ostruthium

THE PRESENTLY KNOWN DISTRIBUTION OF FUROCOUMARINS () IN * M. A. PATHAK, Pn.D.**, FARRINGTON DANIELS, JR., M.D.*** AND T. B. FITZPATRICK, M.D.** The recent use of compounds (1) in(including psoralen and ) were the the treatment of and as a means ofmost effective antifungal agents among seventeen natural derivatives tested. Some hither- increasing the tolerance of human skin to solarto unreported results of Dolcher, Rodighiero and radiation and increasing the pigmentationCaporale have been mentioned by Musajo (8): which follows exposure to radiationthey described the mutagenic properties of five illustrates how ancient medical lore may some-furocoumarins and found 5-methoxypsoralen and times be modified to satisfy present-day demands.psoralen to be almost as effective mutagenic agents as is light-sensitized trypafiavin. Altenburg The furocoumarins, more commonly known as(9) reports that psoralens increase the mutation psoralens, are pharmacologic agents which, withrate in drosophila. modern technics, can be isolated from herbal During the last three decades an increasing number of reports have been published about a remedies that have been employed for manyform of dermatitis in man which follows contact centuries (2). Concomitantly with recent prog-with many plants and subsequent exposure of the ress in the synthesis of new organic moleculesskin to sunlight (10, 11, 12, 13). It has long been for therapeutic purposes, interest in manyknown that photosensitization dermatitis with ancient drugs and herbal concoctions has beenresidual pigmentation develops in skin which has come into contact with figs, cow , wild revived because some of these medicaments haveparsnip, wild , , , , been found to contain specific pharmacologicalcoriander, angelica, and several other agents which exert scientifically recognizableplants. The condition has also been described in therapeutic effects. individuals exposed to the oil of Persian limes (14) and among carrot processers (13, 15). Recently Furocoumarins (psoralen, 8-methoxypsoralenthe due to furocoumarins (xanthotoxin) and 5-methoxypsoralen (bergap-has become a public health problem among ten)) occur naturally in the leaves, roots and fruitpickers (16). This phytophotodermatitis, as well of plants which have been used for centuries inas that which follows contact with plants of other India, Egypt and other oriental countries (2) forspecies, is thought to be caused largely by furo- the treatment of vitiligo. Fowiks et at. (3) havecoumarin compounds which are characteristically reported that furocoumarins exert a photosensi-present in these plants. The occurrence of furo- tizing effect on bacteria in the presence of long- in many familiar edible plants, and the wave ultraviolet light. In a later publication,widely recognized photosensitizing action of these Fowiks (4) has also pointed out that these com-compounds have recently led the authors (17) to pounds belong to a group of substances whichstudy the mechanisms of photosensitivity and can inhibit certain aspects of growth with-photodynamic action in detail. Whether the skin out otherwise harming the plant; he has furthercan be photosensitized by ingestion of natural postulated that furocoumarins may act as naturalfurocoumarin containing foods has not yet been growth regulators in certain plants (5, 6). Chakra-established. borty et al. (7) have shown that the psoralens Several clinical manifestations of phytophoto- dermatitis have specific names: e.g., "berloque *Fromthe Research Laboratories of thedermatitis" which is the reaction to 5-methoxy- Department of Dermatology of the Harvardpsoralen present in the oil of Bergamot used in Medical School at the Massachusetts Generalcertain perfumes (10, 18, 19, 20); and "dermatitis Hospital, Boston 14, Massachusetts and the De-bullosa striata pratensis" (21, 22, 23, 24) which partment of Dermatology of the University offollows exposure of the skin to sunlight after it Oregon Medical School, Portland, Oregon. has come into contact with "meadow grass" (in **Presentaddress; Dept. of Dermatology Mass. most cases Agrimony eupatoria). General Hospital, Boston 14, Mass. Several publications dealing with dermatitis 5*5Presentaddress: Division of Dermatology Cornell University Medical School, New York,caused by plants and eau de cologne have ap- N.Y. peared in European and American dermatologic This work was supported by Grant CY-2837journals. A large number of these deal with the (C-2 and C-3) P. E. T., and Grant #CY-5003 (C-i)erythemal response and hyperpigmentation asso- from the National Institutes of Health, Unitedciated with sea bathing and outdoor sun bathing States Public Health Service. on clear sunny days after the application of eau Received for publication November 24, 1961. de cologne. It is known that several perfumes 225 TABLE 1 Distribution of Furocoumarins in Nature

No. Compound and Structure Natural Sourres Common Name Family References

Psoralen Psoralea corylifolia Babachi Leguminosae 27, 28, 29 (Ficusin) Ficus carica Fig Moraceae 28, 30, 31 0 Coronilla glauca Leguminosae 8, 32 Phebalium argenteum 33, 34 ' ' 1 2 Xanthoxylum flavum West Indian satin 35 WOO d a 2. 5-Methoxypsoralen Ficus carica Fig Moraceae 8, 28, 30, 36, 37, (, Majudin, ileraclin) 38, 39 Z Fagara xanthoxyloides Artar prickly ash Rutaceae 28, 37, 40 0 Skimmialaureola Neera Rutaceae 8, 28, 37, 41 ,.7 bergamia (Risso) Bergemot oil Rutaceae 8, 28, 37, 42 J j Rue Rutaceae 8, 38, 39, 43, 44, 45 Citrus limonum Lemon Rutaceae 38 0C112 Citrus acida Rutaceae 37, 46 Fagara schinofolia Rutaceac 47 Ligusticum acutifolium ljmbelliferae 8, 28, 37 acutilobum Umbelliferae 48 Ligusticum N sphondylium Cow parsley Umbelliferae 8, 28, 37, 39, European cow parsnip N Heracleum giganteum IJmbelliferae 8, 37, 39 majus Linn Bishop's weed I.Jmbelliferae 50 Heracleum nepalense Ilmbelliferae 8, 39 Seseli indicum Hoegen celery IJmbelliferae 8, 26, 37, 39 Pastinaca sativa Garden parsnip IJmbelliferae 8, 30, 51 Heracleum lanatum Cow parsnip Umbelliferae 52 Angelica, Engel- Umbelliferae 53, 54 wurz Bishop's weed Umbelliferae 39, 50 Pimpinella magna Umbelliferae 8, 39 Pimpinella saxifraga Cow parsnip lJmbelliferae 8, 28, 37, 39, 55, 56 Petroselium sativum Garden parsley Umbelliferae 8, 39, 57 3. 8-Methoxypsoralen Ammi majus Bishop's weed IJmbelliferae 50, 58, 59, 60, 61 (Xanthotoxin or Methoxalen or Ammoidin) Angelica archangelica Engelwurz lJmbelliferae 52 Pastinaca sativa Garden parsnip IJmbelliferae 51 00H3 Ficus carica Fig Moraeeae 38 0 Ruta chalepensis Rutaceae 8, 28, 37, 39, 41 Fagara xanthoxyloides Rutaceae 28, 29, 40, 62 70(IV0/ Ruta montana Rutaceae 8, 39, 63 Aegle marmelos Bel Rutaceae 64 Ruta graveolens Rue Rutaceae 8, 38, 39, 44 Luvanga scandens Lavanga Rutaceae 65 Xanthoxylum flavum West Indian satin Rutaceae 35 '-3 wood Ruta bracteosa Rutaceae 41 4. 8-Isopentenyloxypsoralen Imperatoria ostruthium Masterwort IJmbelliferae 28, 37, 66 (Imperatorin or Ammidin) Hog fennel z Umbelliferae 28, 37, 64 Angelica glabra C Angelica archangelica Engelwurz IJmbelliferae 28, 37, 67 OH3 Ammi majus Umbelliferae 59, 60, 61 / ostruthium Masterwort Ijmbelliferae 28, 29 OCH2—CH=C Pastinaca sativa Parsnip IJmbelliferae 37 C \ Prangos pabularia Umbelliferae 37, 76 C OH3 Aegle marmelos Bel Rutaceae 37, 68, 69 Ruta chalepensis Rutaceae 53 /O\1/O\\/V 5. 5,8-Dimethoxypsoralen Pimpinella saxifraga Oow parsnip Umbelliferae 28, 37, 70, 71 () Heracleum sphondylium Oow parsley IJmbelliferae 28, 37, 72 Sesli indicum Hog celery lJmbelliferae 28, 37 00H3 Skimmialaureola Neera Rutaceae 41 Oitrus aurantifolia West Indian lime Rutaceae 37, 73 oil Luvanga scandens Rutaceae 65 I_11//V montana Rutaceae 5 Fagara oilanthoides Rutaceae 74 00H3 Heracleumlanatum (var. Rutaceae 52 nipponicum) Oitrus acida Lime Rutaceae 46

-4 TABLE 1—Continued

No. Compound and Structure Natural Sources Common Name Family References

6. 5-Isopentenyloxypsoralen Masterwort Umbelliferae 28, 29, 37 (Isoimperatorin) Imperatoria ostruthium Masterwort TJmbelliferae 28 Pastinaca sativa Garden Umbelliferae 75 /"\ /\/0 parsnip CH LHL)OCH2—CH=C CH3 7. Prangenine Prangos pabularia Tlmbelliferae 76 / 0 0 /°N/I z

I U) 0CH2(CH2)2CH3 8. 4'-Methoxy,-S'-isopropylpsoralen Peucedanum offleinale Masterwort lJmbelliferae 28, 77 s. (Peucedanin) Prangos pabularia IJmbelliferae 37 H3C H / C 0 H3C \/U\/\I

9. 5-Epoxy isopentenyloxypsoralen Peucedanum offleinale Masterwort TJmbelliferae 28, 29, 37 (Oxypeucedanin) Peucedanum ostruthium Masterwort Umbelliferae 37 Prangos pabularia lJmbelliferae 37 / 0 \/0 Imperatoria ostruthium Masterwort lJmbelliferae 8 Ii /I OCH2—CH—C—(CH3)2 0 10. Oreoselone Peucedanumofficinale Masterwort TJmbelliferae 29 Peucedanumoreoselinum 78 H30 ' /0 113 11. Ostruthol' Peucedanum ostruthium Masterwort Umbelliferae 28, 29, 37, 79 (ii/\ /N/0

OCH2CH—C(C113)2 ()H OCOC===CH CU3 CH3 12. 5-Methoxy,8-isopentenyloxypsoralen Angelica glabra Umbelliferae 29 (Phellaptorin) Phellopterus littoralis Umbelliferae 29 CU3 OCH2CH=C" -4 /0\/0\/OCH3 Z

13. 4',5-dihydro,5'(-1-glucosoxy-isopropyl)psoralen Peucedanum decursivum Umbelliferae 37, 80 (Nodakenin) H3C 0C6H1105 / 0 H3C/ NJ 112 TABLE 1—Continued No. Compound and Structure Natural Sources Common Name Family References 14. Aglucone of nodakenin Peucedanum decursivum Umbelliferae 37, 80, 81, 82 (Nodakenetin) H CH2OH /C/O 0 113C

15. Psoralidin Psoralea corylifolia Bavachi Leguminosae 83 5'i C11=C CH2 (CH3)2 0'-4

16. L1JJ 5-Hydroxypsoralen Citrus bergamia (Risso) Bergamot oil Rutaceae 28, 29 (Bergaptol) Citrus aurantifolia West Indian lime Rutaceae 37, 42, 73 oil z 0 /O\ /O\/ 02

17. 8-Hydroxypsoralen Angelica archangelica Engelwurz TJmbelliferae 28, 29, 37, 67 () OH /\ /\( 0 18. LQ5-Methoxy-8-epoxyisopentenyloxypsoralen Angelica glabra Byakusi (Japanese IJmbelliferae (Byak angelicol) ivy) 0 C113 o CH2—CH——C 0 IL/ \/I \ C113 19 5-Methoxy-8-(2, 3-dihyclroxy) -isopentyloxypsoralen Angelica glabra Byakusi (Japanese TJmbelliferae 37 (Byak ) ivy) OH OH O C112—CH—C(CH3)2 0 Li/O\ /O\, CH3 20. 5-Geranyloxypsoralen Citrus aurantifolia Bergamot oil Rutaceae 28, 33, 37 (Bergamotin) Persian lime 1 0 z

OCH2CH

(1 0 HC—C—CH2CH=C(CH3)2 21. Isopsoralen Psoralea corylifolia Bavachi Leguminosae 37, 84, 85 (Angelecin) Angelica glabra Umbelliferae 37, 52, 86 e z

1/\/ I I I I Z 22. 5-Methoxyisopsoralen Pimpinella saxifraga Cow parsnip Umbelliferae 28, 37, 71, 80 (Isobergapten) Heracleum sphondylium Bibernell T]mbelliferae 28, 37, 70, 71, 72 Heracleum lanatum Cow parsnip Umbelliferae 52 j\ 00 Pimpinella magna Umbelliferae 8

0 CHa TABLE 1—Concluded

No. Compound and Structure Natu ral Sources Common Name Family References

23. 5,-6-Dimethoxyisopsoralen Pimpinella saxifraga Cow parsnip Umbelliferae 28, 37, 70 (Pimpinellin) Heracleum sphondylium Cow parsley Tjmbelliferae 28, 37 Pimpinella magna Umbelliferae 8 00 Heracleum lanatum Umbelliferae 52 o)/I "( H3CO/L) OCH3 24. Oroselon Peucedanumoreoselinum Umbelliferae 78, 87

H2C / I\ 0 0 H3C" _(c/ \/ LVJL 25. 6-Methoxyisopsoralen Pimpinella saxifraga Cow parsnip Umbelliferae 55, 56 (Sphondin) Heracleum sphondylium Umbelliferae 28, 29, 72 Rutaceae 5 Heracleum lanatum Rutaceae 52

H3CO 26. Thamnosmin Thamnosma montana Rutaceae 5 \ 00 /\0 I (CH3)2CHCH2CO/ I 0CH5 , 27. 4', 5'-Dihydro-5'- (1-hydroxyisopropyl), 4'-hydroxy- Athamanta oreoselinum Umbelliferae 87 diisovaleryl ester Peucedanumoreoselinum Umbelliferae 29, 87 (Athamentin) H, C

,C—OCOCH,CH(CH,), OCOCH,CH(CH,), C/ / " 0 /\ H2 \_I /o\/0 234 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 2 Plants Reported to Evoke Phytophotodermatitis

Common Name Natural Order Referenres

Fig Ficus earica Moraeeae 10, 26 Parsnip Pastinaca sativa Umbelliferae 21, 22, 88, 89 Cow parsnip Heracleum sphondylium Tlmbelliferae 10, 25, 90 Garden parsnip Heracleum gigantum lJmbelliferae 13, 91, 92 Wild parsnip Pastinaea sativa lJmbelliferae Heraeleum mantegazzianum Fennel Foeniculum vulgare Umbelliferac 10, 13 Anethum graveolens Umbelliferae 10, 11, 13 Parsley Peucedanum oreoselium IJmbclliierae 10, 11, 13 Wild carrot Daucus earota Umbelliferac 10, 11, 13 Garden carrot Daueus sativa Umbelliferae 15, 93 Masterwort Peucedanum ostruthium Umbelliferae 25 Celery Apium graveolens Umbelliferae 16, 88, 94 Atrillal Ammi maj us Umbelliferae 95 Angeliea Angelica Umbelliferae 13 Common rue Ruta graveolens Rutaceae 10,96 Gas plant Dictamus albus Rutaeeae 97 Lime bergamot Citrus bergamia Rutaeeae 10, 11, 13 Dictamnus fraxinella Rutaceae 10 Lime Citrus aurantiom Rutaceae Rutaceae Lime Citrus aurantifolia Rutaeeae 10,14 Persian lime (Tahitian,Citrus aurantifolia, var. Swingle Rutaceae 10, 14 Bearss) Buttercup Renuneulus species Renunculaceac 10, 13 Mustard Brassiea species Cruciferae 11, 13 Sinapsis arevensis 98 Blind weed Convolvulus arevensis Convolvulaceac 10, 11, 92 Agrimony Agrimony eupatoria Rosaeeae 10,13 Yarrow (mill oil) Achilleae millefolium Compositae 10 Goose foot Chenopodium species Chenopodiaeeae 11, 13, 99 Bavaehi Psoralea coryilolia Leguminosae 25, 95 St. John's wort Hypericum perforatum Hypericaceae 13 Hypericum concinnum contain fluorescent materials some of which aresources of light were used. Klaber thus foretold furocoumarins. experimental difficulties to be encountered years In 1942, Klaber (10) suggested the term "phyto-later. photodermatitis" for the reaction to sunlight of The work of Kuske (25) merits review because it skin which has been in contact with certain species established the relationship between the chemical of plants. He reviewed the evidence that wave-components of certain plant tissues and the lengths of ultraviolet radiation between 3,200 anddevelopment of phytophotodermatitis. Kuske 3,800 A (0.32—0.38 micron) were required to initiate reviewed the earlier proposal of Kitchevatz (26) the reaction, and emphasized the futility of test-that chlorophyll is the photosensitizer in exoge- ing with mercury-are lamps. He stated that, whennous percutaneous photosensitization; he also a mercury-vapor lamp was employed, the reactionstudied the latent period, the intensity and the could only be demonstrated after filtration throughresidual effects of the reaction produced by fig windowglass. He reported that if the shorter ul-extracts, and described the residual effects as traviolet rays were not thus filtered off, the cry-intense, persisting pigmentation. In experiments thema produced by these alone precluded a dosewith plant extracts, Kuske obtained mild of the longer rays sufficient to excite the phyto-erythema due to photosensitization reactions to genie reaction. This no doubt explains the failurePastinaca sativa, Ficus carica and Angelica offici- of many observers to reproduce berloque dermati-nails, and severe (blister formation) reactions to tis and other types of this reaction, when artificialRuta graveolens and Heracleum niantecazzianum. DISTRIBUTION OF FUROCOUMARINS IN PLANTS 235

He pointed out that the presence of certain chemi- Various investigators have studied the photo- Lal substances in plants tends to follow botanical classifications and that the Rutaceae, Umbellif-sensitizing action of many naturally occurring erae and Moraceae are capable of evoking photo-furocoumarins and their synthetically prepared .sensitization reactions. With Dr. Mickelmann,derivatives in human skin, guinea-pig skin and Kuske identified the photosensitizing compoundsbacteria (3, 8, 100, 101, 102, 103). Not all of of the furocoumarin group and studied the reac-the naturally occurring furocoumarins tested tion of normal skin to solutions of bergapten (5-methoxypsoralen) and oxypeucedin. In hiswere found to produce photosensitization. When experiments, allergic factors were eliminated asapplied topically, imperatorin, isopimpinellin, causes of the reactions observed because the reac-oxypeucedanin, bergaptol, xanthotoxol, angele- tions occurred in all individuals. cm, isobergapten and pimpinellin do not induce This survey of the literature has been made in an attempt to determine how widespread the dis-erythema. Psoralen, xanthotoxin, bergapten, tribution of furocoumarins is in plants. Table 1isoimperatorin and bergamotin, on the other shows the distribution of these substances inhand, have been found to be biologically active. plants, in so far as it has been reported in availableMany others still remain to be tested, e.g., publications. A list of plants which are known toprangenine, peucedanin, sphondin, oreoselone, cause phytophotodermatitis constitutes Table 2. Existing data obviously do not indicate whethernodakenetin, psoralidin, phellaptorin, nodakenin, plants not mentioned in the literature wereoroselon, thamnosmin, byak angelicol, byak omitted from lists because they contain no furo-angelicin, athamentin, etc. coumarins or because their chemical components The data presented in Table 2 show that have not been identified. Table 1 lists the moremembers of Umbelliferae are outstanding in common of the psoralen derivatives, the botanical, and in some cases the common name of the plantscausing photosensitization contact dermatitis. in which they occur, the family to which theseContact with wild , fennel, caraway, plants belong and the sources from whieh theanise, corriander, celery, angelica species, wild data were obtained. Table 2 is a list of plantsparsnip, parsley and several other plants is well that have been reported to induce phytophoto- dermatitis. As can be seen, about 50 per cent ofknown to cause photosensitization (10, 11, 12, these belong to the order Umbelliferae. Next13). The members of the Rutaceae also fre- most numerous are the Rutaceae. Single membersquently induce phytophotodermatitis. They of the Moraceae, Renunculaceae, Cruciferae,include the common rue, gas plant, and several etc. are also included. No claim is made that thevarieties of lime and other citrus fruits, and listing in either table is complete. bergamot. In the Moraceae family the fig has DiscussIoN been known for a long time to have a photosen- As can be seen in Table 1, only four or fivesitizing action. Other botanical families asso- major plant families have been found to containciated with photosensitization are Convol- furocoumarins. The Umbelliferae and Rutaceaevulaceae, Compositae, Cruciferae, Rosaceae are the largest and most important of these; theand Renunculaceae. Leguminosae and Moraceae include few but The etiology of this phytophotosensitization widely distributed species. Geissman and Hin-has not been established. One thing is clear, i.e., reiner (37) have proposed a mechanism of bio-that light, particularly in the region of 3200— genesis of furocoumarins in the various plant3800 A, plays an important part (14, 92, 104). species and have suggested that they owe theirThe observations related to the action spectrum formation to biochemical processes whichof 8-methoxypsoralen which have been reported characteristically occur only in certain generaby Buck et at. (105) and Pathak (104) indicate and families. It is not surprising, therefore, thatthat the wavelengths which most effectively furocoumarins seem to be present in plantsevoke the erythemal photosensitization response which belong only to a few plant families. are in the range between 340 and 380 m, with The furocoumarins listed in Table 1 weremaximum effectiveness at 360 mi. Various extracted from various parts of the plant, e.g.,plant species reported to cause photosensitiza- leaves, seeds, fruits, roots and rhizomes, Thesetion (Table 2) have been analyzed by several compounds are most abundant in plants whichworkers and shown to contain furocoumarins, have flowered and in ripe seeds and fruits; duringespecially xanthotoxin, bergapten, psoralen, the early stages of plant growth their presenceetc. These compounds are highly photosensit- is not easily recognizable. izing and cause dermatitis and residual pig- 236 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY mentation. It is therefore not surprising that BosE, P. K.: On the antifungal action of some natural aoumarins. Ann. Biochem. several species of Umbelliferae, Rutaceae, etc. Exp. Med., 17: 57, 1957. have been implicated in phytophotodermatitis. 8. Musuo, L.: Interessanti proprieta delle It is possible that other plants which have not furoeumarine naturali. IiFarmaco, Ed. Sci.,10: 1, 1955. yet been analyzed may constain active furo- 9.ALTENBUEa,E.: Studies on the enhancement coumarins and could become the major causes of the mutation rate by carcinogens. of skin sensitization in the presence of light, TexasRep. Biol. Med.,14: 481, 1956. 10. KLAEER, H.: Phyto-photo-dermatitis. Brit.J. giving rise to erythema and subsequent residual Derm., 54:193, 1942. pigmentation. 11. BELLEINGER, H. E.: Phyto-photo-dermatitis. Brit. Med. J.,1:984, 1949. 12. GOLDsMITH, W. N. AND HELLIER, F. F.: sUMMARY Recent Advances in Dermatology, second In this review, we have attempted to outline edition. New York, Blakiston Company, Inc., 1954. the distribution of photosensitizing furocou- 13. KLAUDER, J. V. AND KIMIvUcH, J. M.: Sensi- marins in the plant kingdom. Available data tization dermatitis to carrots. A.M.A. Arch. Derm., 74: 149, 1956. indicate that they are found in the orders 14. SAM5, W.M.: Photodynamic action of lime Ijmbelliferae, Rutaceae, Moraceae and Legumi- oil(Citrus aurantifolia). A.M.A. Arch. nosae. Various plants implicated in the causation Derm.,44:571, 1941. 15. PECK, S. lvi., SPOLYEE, L. W. AND MASON, of photosensitization dermatitis (phytophoto- H. S.: Dermatitis due to carrots. Arch. dermatitis) belong to the orders IJmbelliferae Derm.Syph., 49:266, 1944. 16. BIRMINGHAM, D. J., KEY, M. M., TUBIdH, and Rutaceae. It is likely that photosensitization G. E. AND PERONE, V. B.: Phototoxic contact dermatitis is due largely, if not entirely, bullae among celery harvesters. A.M.A. to the action of photosensitizing compounds Arch.Derm., 83: 73, 1961. 17.PATHAK, M. A., ALLEN, B., FELLMAN, J. H. related to furocoumarins. The distribution of AND INGRAM, D. J. E.: Photosensitization furocoumarins in plants is probably far more and the effect of ultraviolet radiation on widespread than the reported incidence of the production of unpaired electrons in the presence of furoeoumarins (psoralens). phytophotodermatitis would lead one to suppose. Biochim. et Biophys. Acta, 54: 506, 1961. For the initiation of phytophotodermatitis, there 18. GRoss, P. AND RoBINsoN, L. B.: Berlock dermatitis, unusual dermatitis and pig- are two requisites: 1) contact with a sensitizing mentation following use of perfume. furocoumarin and 2) subsequent exposure to Arch. Derm. Syph.,21:637, 1930. ultraviolet radiation of wavelengths greater 19.GOODMAN,H.:Perfume dermatitis. Brit. J. Derm., 43: 177,1931. than 3200 A (usually sunlight). It is to be 20. SzANT6, J.: Pigmentationen der Haut, anticipated that more specific varieties of phyto- entstanden durch die sensibilisierende photodermatitis will be recognized as more Wirkungaromatischer Ole. Derm.Wschr., 45:1820, 1929. photosensitizing compounds are identified. 21.OPPENIIEIM, M.: Dermatite bulleuse striée consecutive aux hams de soleil dans les REFERENCES pres (dermatitis bullosa striata pratensis). 1. Symposium: Psoralens and radiant energy. Ann. Derm. Syph., 3:1,1932. Suppi., J. Invest. Derm., 32,Part II: 22. OPPENHEIM, M.: Dermatitis striata pratensis 132—391,1959. bullosa (grass or meadow dermatitis). 2.FITZPATRIcK, T. B. AND PATRAK, M. A.: Arch. Derm. Syph., 46: 541, 1942. Historical aspects of and 23. O'DONNOYAN, W. J.: Dermatitis bullosa other furocoumarins. J. Invest. Derin., 32, striata pratensis. Agrimony dermatitis. PartII: 229,1959. Brit.J. Derm., 54: 39, 1942. 3. Fowucs, W. L., GRIFFITH, D. G. AND 24. LEE, H. G.: Dermatitis bullosa striata OGIN5KY, E. L.: Photosensitization of pratensis. Proc.Roy. Soc. Med.,40: 14, bacteria by furoeoumarins and related 1946. compounds. Nature, 181: 571, 1958. 25. KU5KE, H.: Experimentelle Tjntersuchungen 4. FowLns, W. 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bilisation de la peau. Bull. Soc. Franc. 45. MUHLEMANN, H.: Coumarin like constituents Derm. Syph., 43: 581, 1936. of Herba rutae. Pharm. Acta Helv., 13: 27. Jois, H. S., MANJUNATI-1, B. L. AND VENKATA 45; 330, 1938. RAO, S.: Chemische Untersuchung der 46. KNASTAGIR, H.: Natural coumarins isolated Samen von Psoralea corylifolia, Linn. I. from the leaves of Citrus acida. J. Indian Chem. Zentr., 104 (II): 77, 1933; Chemical Chem. Soc., 24: 421, 1947. examination of seeds of Psoralea corylifolia. 47. NAKAOKI, T. AND MORITA, N.: Constituents J. Indian Chem. Soc., 10: 41, 1933. of the fruits of Fagara species of Japan. 28. SPATH, E.: Die naturlichen Cumarine. Ber. J. Pharm. Soc., Japan, 73: 770, 1953. Deut. Chem. Ges., 70 A: 83, 1937. 48. KARIYONE, T. AND KANNO, M.: Constituents 29. SETHNA, S. M., AND SHAH, N. M.: The chem- of the fruits of Ligusticum acutilobum, istry of coumarins. Chem. Rev., 36: 1, Sieb. et Zucc. I. J. Pharm. Soc., Japan, 1945. 56: 662, 1936. 30. 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64. MUKEEJI, B.: Psoralea and other indigenous decursivum Maxim. Ber. Deut. Chem. Ges., drugs used in leucoderma. J. Sci. Indust. 69 B, 2062, 1936. (German) Res., 15 A: 1, 1956. 83. CHAKRAVARTI, K. K., BOSE, A. K. AND SID- 65. BOSE, P. K. AND MOOKEBJEE, A.: On the DIQUT, S.: Chemical examination of seeds constitution of natural coumarins isolated of Psoralea corylifolia. J. Sci. Indust. Res., from Luvanga scandens (Lam). J. Indian 7 B, 24, 1948. Chem. Soc., 21: 181, 1944. 84. Jois, H. S. AND MANJUNATH, B. L.: Identity 66. SPATE, E. AND HOLZEN, H.: Plant fish poi- of isopsoralen, a constituent of the seeds sons. V. Constitution of imperatorin (from of Psoralea corylifolia L., with angelicin Imperatoria ostruthium). Ber. Deut. Chem. from the roots of Angelica archangelica L. Ges., 66 B: 1137, 1933. (German) Ber. Deut. Chem. Ges., 69 B: 964, 1936; 67. SPATH, E. AND VIERHAPPER, F.: Natural Proc. Indian Sci. Congr., 21: 243, 1934. coumarins. XXIII. 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101. PATHAK,M. A., FELLMAN, J. H. AND KAUF- constitution and photodynamic properties MAN, K. D.: The effect of structural altera- of furocoumarins. Farmcco (Pavic), Ed. tions on the erythemal activity of furo- Sci., 13: 355, 1958. (Italian) coumarins: psoralens. J. Invest. Derm.,104. PATHAK, M. A.: Mechanism of psoralen 35:165, 1960. photosensitization and in vivo biological 102. MU5AJ0,L.,RonIGHIEao,G.ANDCAFORALE, action spectrum of 8-methoxypsoralen. J. C.: L'activité photodynamique des con- Invest. Derm., 37:397, 1961. marines naturelles. Bull. Soc. Chim. Biol.,105. BUCK, H. W., MAGNU5, I.A. ANnPORTER, 36: 1213, 1954. A. D.: The action spectrum of 8-methoxy- 103. MusAjo, L., RODIGHIERO, C.,CAPORALE,C. psoralcn for erythema in human skin. ANnANTONELLO, C.: Relation between Brit. J. Derm., 72: 249, 1960.