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THE TOXIC PRINCIPLE OF POISON IVY' CHARLES R. DAWSON Columbia University, New York, N. Y.
PoIsIoN ivy is probably the most widely known of all North American poisonous plants. The painful irritation, inflammation, and blistering of the skin that follows contact with the plant is an experience that a great many people suffer every year. Sensitivity to the plant varies widely from one individual to another. Highly sensitive individuals on slightest contact with the plant often develop a poison ivy dermatitis condition so severe as to require hospitalization. There are three varieties of the species R h u s toxicodendron that are responsible for the majority of poison ivy-like dermatitis cases in this country. They are poison ivy ( R h u s toxicodendron radicans), poison oak ( R h u s toxicodendron diversilobum), and poison sumac ( R h u s toxicodendron vernix). All three belong to the Anacardiacea family of plants, members of which are found in mauy parts of the world. Two other interesting members of this family are the lac tree (Rhus verniciJEua) found in Japan, China, and Indo-China and the cashew nut tree (Anaeardium occidentale) found in India, East Africa, and Central and South America. Poison ivy is particularly abundant in the northeastern quadrant of the United States and in southeastern Canada, whereas poison oak is most commonly encountered in the western United States and northern Mexico. Poison sumac is commonly found in the swamp regions of t,he southern aud east.ern Unit,ed States. CHEMICAL STRUCTURE OF THE ACTIVE PRINCIPLE
There has long been an interest in determining the chemical structure of the active principle of poison ivy. The first chemical investigation was made by Khittel (1) a little less than 100 years ago, and about 20 years ago the carbon skeleton of the active principle was es1 Abstrsot of an address prenented a t the 17th Summer Canierenee of the New England Association of Chemistw Teachers at Tufts Univoraity, Mdford, Mns~nehunnt~ta, Aogost,, 19.53.
tablished by Hill and his students at Wesleyan University (2). During the period from 1906 to 1922 the work of Majima and associates in Japan, on the chemical nature of the vesicant material in the sap of the Japanese lac tree, was outstanding. They extracted from the sap a highly active yellow oil which gave typical catechol reactions. Majima called the yellow oil Urushiol and observed that it was unsaturated. He proved that the hydrogenated form, hydrourushiol, had the structure of 3-pentadecylcatechol and he also synthesized a number of derivatives (3). His attempts to locate the positions of the olefinic bonds in the lifteencarbon side chain of urushiol led him to conclude that urushiol was a mixture of hydrourushiol and three olefinic components which he could not separate by methods available at that time. He proposed structures for the three olefinic components on the basis of ozonolysis studies made on the mixture (4). However, recent work a t Columbia by Sunthankar has shown that two of the olefinic structures proposed by Majima must be modified (5). In 1934, Hill a t Wesleyan University recognized that the toxic oil extractable from poison ivy was very similar in properties to the Japanese lac urushiol ( 2 ) . The yellow oil upon catalytic hydrogenation, methylation, and acylation gave compounds having the same physical constants, toxicity, and elementary analysis as those reported by Majima after hydrogenation of urushiol. These results have led to the widespread impression that the poison ivy principle and .Japanese lac urushiol are identical. Such a conclusion, however, is not justified on the basis of Hill's results which established only the ident,ity of the hydr~genat~ed forms of the two oils. Recent invest,igations a t Columbia University have shown that the poison ivy principle is a mixture of four components, all having the structural skeleton of the minor and sat,urat,ed component, 3-pentadecylratechol
VOLUME 33, NO. 2, FEBRUARY, 1956
95
(hydrourushiol) (6). I n this way the poison ivy oil is similar to the lac urushiol. However, the poison ivy principle and the lac urushiol are not identical (5). The higher olefinic components of the two oils do not have the same structures, and they do not appear to be present in the same relative amounts. During the past war we had an opportunity a t Columbia to work for several years on the structures of the alkenyl phenols present in cashew-nut shell liquid (7-11). The oil in the shell of the nut is almost completely phenolic in composition and contains three differentphenols-anacardic acid, cardanol, and cardol. Each of these phenols possesses a ateen-carbon side chain having an unsaturation equivalent to about two olefinic bonds. Large amounts of the shell liquid are brought into this country annually for the manufacture of phenolformaldehyde type resins. These resins have unusual electrical insulation properties and were used during the war in the insulation of fighter aircraft and signal corps equipment. The government was concerned with the hazards associated with handling the shell liquid and its products. Periodically the factory personnel, the stevedores, or an airplane mechanic would come down with a mysterious case of what looked like poison ivy dermatitis. Our investigations with Dr. H. Keil revealed that the minor resorcinol component cardol was the source of the trouble (8). Of great interest to us during these studies on cashewnut shell liquid was the fact that in cardanol, the monophenolic and main component, we had available in large amounts a naturally occurring alkenyl phenol possessing a CldHn side chain-possibly similar to that in urushiol and the poison ivy principle. Our early experiments with Sletzinger (10) and Izzo (11) nsing the methylated form of cardanol convinced us that it was heteroolefinic in make-up. Symes then found that it could be cleanly separated into a saturated, mono-, di-, and triolefinic component by means of chromatography on activated alumina. The structures of the olefinic components were then determined by ozonolysis and oxidative degradations (12). The experiences gained and techniques developed using the abundantly-available alkenyl phenols of cashew nut shell liquid made possible and attractive a reinvestigation of the olefinic character of the poison Poison ivy leaves and twigs Dimethyl "urushiol": nK 1.5032, double bond value = 2 . 0
ivy principle. The allergenic properties of the poison ivy oil, its marked susceptibility to autoxidation, and in particular our previous experience with the chromatographic separation of the alkenyl phenols of cashewnut shell liquid made it advisable t o work with the relatively more stable and nontoxic dimethyl ether rather than the free catechol. The dimethyl "urushiol," obtained as shown below, was essentially free of non-"urushiol" contaminants, for on catalytic hydrogenation it absorbed approximately two moles of hydrogen and gave practically a quantitative yield of pure dimethyl hydrourushiol of sharp melting point. The fact that the dimethyl "urushiol" was not a homogeneous diolefin became readily apparent when it was chromatographed on a column of activated alumina (16). The fractions of oily liquid obtained either by fractional elution or by extrusion and sectioning of the column showed a parallel increase in double bond value and refractive index very similar to that observed earlier with the alkenyl phenols of cashewnut shell liquid. Frartions of similar refractive indices were combined and rechromatographed. I n this may chromatographically pure samples of a monoolefin, a diolefin, and a triolefin were obtained. The saturated component crystallized out of the earliest fractions coming from the column, i. e.. those least strongly absorbed. Each of the olefinic components absorbed the calculated amount of hydrogen on catalytic reduction to give pure 3-pentadecylveratrole (dimethyl hydrourushiol). No fraction with a double bond value exceeding 3.0 was obtained from any of the chromatograms. The crystalline saturated component, present only in small amounts in the poison ivy principle (about 5 per cent), was identified as 3-pentadecylcatechol (hydronrushiol) by comparison of its properties with an authentic sample obtained by synthesisand by the hydrogenation of the poison ivy oil. The positions of the double bonds in the mono-, di-, and triolefinic components were established by Symes (6) using ozonolysis and other standard methods of oxidative degradation. The structures of the four components of the poison ivy principle are: OH Saturated component
extract alcohol, eta. distill
Crude "urushiol": methylate, Na CH.1, szptponiiy
1
L
+
Crude dimethyl ether
OH Monoolefinic component
170-180' (0.5 mm.)
nialefinic component OH
JOURNAL OF CHEMICAL EDUCATION Triolefinic component OH
CLINICAL INVESTIGATION
the first time, by synthesis, pure samples of 3-pentadecylcatechol, the saturated component (16). More recently Loev has extended and modified the route of synthesis so that it could be successfully applied to the synthesis of the mono-olefinic component (17). Loev also synthesized a number of related compounds for clinical investigation. Dr. Keil's clinical investigations with the crystalline and relatively st,able 3-pentadecylcatechol (PDC) have shown that it can be used as a staudard agent for the diagnosis of poison ivy sensitivity and for investigating the relationship between chemical structure and poison ivy dermatitis activity (18). He recommended the use of PDC in the treatment of poison ivy dermatitis and explored its use as a desensitizing agent. At the present time clinical work on PDC and a number of ot,her compounds synthesized in our laboratories is being directed by the Lederle Laboratories Division of the American Cyanamid Company, who have supported our work for a number of years. I n this program, the clinical investigations by Dr. Albert ICligman and his associates at the University of Pennsylvania, on the use of PDC as a desensitizing agent, have produced most interesting aud promising results. Many individuals who were formerly highly sensitive to the poison ivy plant have been successfully desensitized by a series of injections of PDC.
At the present time very little is known with certainty as to how these substances bring about the charact.eristic blistering, edema, and irritation or rash. Only limited information is available concerning the relationship between structure and activity. Regarding the latter, two types of activity must be differentiated. An alkenyl phenol may be active in the sense that it produces a "poison ivy-like" dermatitis on people already sensitive. I t may also be active in the sense that it induces sensitization in persons not previously sensitized. A compound which is active in one sense may not necessarily be active (or as active) in the other. Dr. Harry Keil conducted clinical work (patch testing) on hnmans in regard to the first type of activity. i. e., producing the dermatitis on previously sensitized individuals. Certain relationships between structure and this activity have been elaborated (IS, 14). 1. The activity is dependent on the free phenolic groups. Met,hylation greatly reduces the activity. 2. The 1,2- and 1,3-dihydric phenols are more active than the 1,4- and the monohydric phenols. LITERATURE CITED 3. The position of the side chain and its length and (1) KH~ITEL, R., Am. J. Pharm., 6 (3), 542 (1858). degree of unsaturation are important. (2) HILL,G. A., V. %~.~~TAcoTTI, AND W. n. GRAHAM, .I. Am. Very little has been done thus far in this field in corChem. Soc.., 56., 2736 (19341. , ~. (3) MAJIMA, R., A N D J. TARARA, &7., 48, 1606 (1915). relating the structure of an alkenyl phenol and its (1) M A ~ I MiAh, d , 55b, 172 (1922). ability to induce sensitization in persons not previously (5) SUNTIIANKAR, S. V.. A N D C. R. DAWSO'I,I. Am. Cham. sensitized. This type of activity is of great interest Soe., 76, 5070 (1954). because of its possible relationship to desensitization. (6) SYMES,W. F., A N D D A W ~ OIN t i d. . , 2959 (1954). Until rerently, none of the pure olefinic components ( WASSERMAN. ) D., A N D DAWSOV, l n d . Enn. Chem... 37,. 396 . i (1945). of poison ivy urushiol were available for clinical in(8) K ~ L II.. , WASSERMAN, A N , ) DAWSON, Ind. !Wed., 14, 825 vestigation. The phenolic methyl ethers which were (1945). se?arated from the natural extract by chromatography (9) WASSERMAR AND DAWSON,J . Am. Chem. Soc., 70, 3675 and nsed for structural characterization of the olefins (1948). M., AND DAWSON,J. 079. Chem., 14, 670 rould not be used clinically because they were inactive. (10) SGETZINQER, (1949). Unfortunately, it is not possible to demethylate the (11) Izso, P. T.AND DAWSON, ibid., 15, 707 (1950). ethers without destroying the olefinic bonds. For (12) SYMESA N D DAWSON, J. Am. Chem. Soc., 75, 4952 (1953). this reason, a method of synthesis for each of the com- (13) ICEIL,WASSERMAN, AND DAWSON, J. E ~ p t l Med., . 80, 275 (1944). ponents of poison ivy urushiol has heen of considerable (14) Ibid., Science, 102, 279 (1945). interest. AND DAWSON, J. O P ~Chem., . 8 , 73 (1945). (15) WASSERMAN Several years ago Wasserman in our laboratories de- (16) Ibid., J. Am. Chem. Soc., 68, 534 (1946). veloped a satisfactory pathway for the synthesis of (17) Lorn, B., Dissertation, Columbia University, 1952. compounds (15) of this type and made available for (18) KEIL,WASSERMAN, A N D DAWSON, J. Allergy, 16,275 (1945). ~
"ATOMIC generating capscity will he doubled every four years betw~en1960 and 1980, according to General Electric Co. In 25 yeam, it was predicted, 23 per cent of d l powor generating plant8 will be atomic." Industrial Research Newsletter
