PLANT SOURCES O F HEPATOTOXIC PYRROLIZIDINE ALKALOIDS L. W . SMITH and C. C. J. CULVENOR CSIRO Diuision of Animal Health, PriLate Bag I , P a r k d l e , I'ic. 5052, Australia
There is increasing recognition that the hepatotoxic pyrrolizidine alkaloids may be of greater importance as a cause of human disease than the presently known outbreaks of poisoning would indicate. The chronic and progressive character of their effects, including carcinogenicity, (1, 2 ) means that in the type of hazard they present, they resemble the mycotoxins rather than the main body of alkaloids. Disease is likely to be induced in man or animals by their ingestion over long periods of time in plants or foods in 11hich they are present at lon concentrations. I n the interests of public health, present knowledge of plant ipecies containing hepatotoxic pyrrolizidine alkaloids .hould be diffused as n idely as possible and brought particularly t o the people n-ho are most at risk. The purpose of this compilation of plant sources is to make the information more readily available t o the health-oriented investigators and educators who have this task. Plants containing pyrrolizidine alkaloids are so numerous and widespread that they can be expected to be present in most environments. The main sources are the families Boraginaceae (all genera), Conipositae (tribes Senecioneae and Eupatorieae) and Leguminosae (genus C r ~ t a l a r i ~the ) , potential number of alkaloidcontaining species being as high as 6000, or 3% of the norld's flowering plant? (3). There have now been several reported outbreaks and occurrences of human poisoning due to these alkaloids, the largest involving more than 2000 people in Afghanistan (4-12). I n these instances, the causative plants nere ingested as medicinal herbs or as weed contaminants of cereal grains. The plants found to be responsible by investigators were not suspected of toxicity by the populations or individuals affected. The early warnings by Schoental (13, 14) about the hazard of pyrrolizidine alkaloids in medicinal herbs were probably overshadowed to a large extent by the discovery of the greater and more ubiquitous hazard of the mycotoxins. However, despite advances in medicine, herbs have remained in use without systematic testing for efficacy or safety even in technically advanced countries. Several such herbs have recently been reported t o contain hepatotoxic pyrrolizidine alkaloids, e.g., comfrey (Symphytum ojiciaale (15, 16), Russian comfrey (S. h: uplandicum), (17), coltsfoot (TussiZago ~ Q Y ~ U ~(18) U ) and petasites (Petasites japonicus Maxim) (19, 20). The recognition of two fatalities in the USA due to consumption of Senecio longilobus as a medicinal herb has led to concern about the extent of use of this herb in Mexican American communities in the USA (21). Still greater human exposure is t o be expected in developing countries where traditional herbal medicines remain in substantial use and ma\- be officially recognized as necessary for a satisfactory level of health care (22). The increasing concern about contamination of foodstuffs with pyrrolizidine alkaloids stems from the experimental findings that at the lowest levels so far administered t o animals, approximately 1-4 ppm of whole diet, chronic liver damage and tumors have been observed (23, 24). The alkaloids of Seitecio jacobaea have been found a t the level of 1-4 ppm in milk ( 2 5 ) and honey (26) from c o m and bees which had been foraging on this species. Some species of 129
JOURKAL OF KATURAL PRODUCTS
130 TABLE
Constituent Alkaloids
APOCYNACEAE Parsonsin eucalyptophylla (F. Muell.) P . heterophylla A . Cunn.
P . spiralis Wall.
P.slraminea ( ( R . Br.) F. Muell.)
Lirechites kar2oinsky . . . . . . . . . BORAGINACEAE Amsinckia hispida (Ruiz et P a v . ) I. PII. Johnston . . . . . . . . . . . . . A . interniedia Fisch e t C . RIey
A . lycopsoides Lehm.
Anchusa arcensis (L.) Bieb.. . . .
44, KO. 2
1. Plants containing hepatotoxic pyrrolizidine alkaloids.
Plant
A . oficinalis L.. .
[VOL.
.
.
...
A s p e r u g o procumbens L. C y n o g l o s s i ~ mnmnbile Stapf & Drummond . . . . . . . . . . . . . .
, , , ,
,
,
,
Ref.
lycopsamine parsonsine het eroph ylline sp/raline sp!ran!ne spiracine lycopsamine loroquin
ae wh wh
28 417 418 418
ae
rt
28 29
intermedine lycopsamine echiumine intermedine lycopsamine echiumine sincamidine intermedine l ycopsamine echiumine echinatine (or diastereoisomer) lycopsamine 7-acet>-llycopsarnine (or diastereoisomer) amabiline (or diastereoisomer)
wh
30
wh
30
w-h
30
wh
31
wh
32 31
wh
31
wh
33, 34
wh n-h
35 33
le
419
wh wh
36 36
le
37
le le
38, 39, 40 41, 42 43
’t, ae
44, 45
le
46 47 34 35 48
amabiline echinatine 7-acetylechinatine .. cynausiine C. australe R . Br.. . . . . cynaustraline echinatine C. creticuni. , . . . . heliosupine amabiline C. glochidintitni Wall. ex Lindl. cynaustraline C. lanceolatiini Forsk.. , . . . . . cynausiine C. lntifoliuni R . Br.. . . . . . . . . . latifoline 7-angelylretronecine heliosupine C. oficinale L.. . . . . . . . . . . echinatine acet ylheliosupine 7-angelylheliot ridine heliosupine c. pictun2 Ait.. . . . . . . . . echinatine pictuniine viridiflorine C. ciridi’oritni Pallas ex Lehm heliosupine Echium i t a l i c u m L.. . . . . . . . . . . . . . . . . echimidine E . plantagineuni L. ( E . lgcopsis L . ) , . echiumine echimidine E . crtlgnre L.. . . . . . . . . . . . . . . heliosupine asperumine lycopsamine (or diastereoisomer) Heliotropiuni acirtij’lorum. . . . helioirine H . aniplericairle Vahl., , , . . . . indicine H . arbainense.. . . . . . . . . . . europine lasiocarpine heliotrine H . arboresrens L. ( H . perirn~ianzimL.) . lasiocarpine ,
Plant Part
If
rt, ae
“t R 11
3e
le ie
49
h-h le le le
31 51 35 119
ie
52
50
MAR-APR
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SMITH A X D CULVESOR :
131
PTRROLIZIDINE ALKALOIDS
TABLE 1. Continued. I
i
Plant
Constituent Alkaloids
H . argueioides Kar. e t Kir.
H.curassaclicuni Linn.. . . .
!
Plant Part
Ref.
-__
I heliot , rine trichodesinine . heliotrine ~
' lasiocarpine angelylhelio t ridine curassavine coromandaline , heliovicine traclielarit hamidine H . dasycarpum Ledeb.. . . . . . . . . . . . . heliotrine
ae ae, rt A'P
53
ae
57
ae ae, rt sd R-h ae ae w-h
58 54 59 63, 61 62 63 61, 65
54, 55
56
~
H . eichwaldi Steud. ex D C . . . , . . . H . europaeum L .
H . indicum L . .
H . lasiocarpum Fisch. e t >\ley.. . , . . . . H . niaris mortui. , . . . . . . . . . . . . . . . H . olgae . . . . . . . . . . . . . . . . . . . . . . . . H . popo.i,ii H. Riedl. subsp. gillianun H. Riedl.. . . . . . . . . . . . . . . . . . . . . . . . H . rainosissimum (syn. H . persicum L., H . undulatum, H . bacciferum). . H . rot%sndifolium... . . . . . . . . . . . . . . H . steidneri I-atke . . . . . . . . . . . . . . . H . supinitm L . . . . . . . . . . . . . . . . . . .
heliot rine lasiocarpine 7-angel ylheliot rine heliot rine lasiocarpine europJne supinine heleurine S- (dihydropyrrolizinome thy1 )-heliot rine chloride mllasiocarpine indicin2d d i c i n e indicinine echinat ine supinine heleurine lasiocarpine heliotrine heliot rine lasiocarpine europine lasiocarpine heliot ririe incanine heliot rine heliotrine europine lycopgamine supniine heliosupine
66, 67 w-h
68
wh ae ae
69
ae
72
ae
73
ae ae ae, rt
'
io
71
74 419 75 76
sd
77
ae ae
78, 79
rt rt wh
80 81 82 83
ae ae ae
51 84
ae
62, 36
ae
62, 63
ae sd
86 75
If
74
7-angelylheliotridine trachelanthic and viridi-
85
JOURNAL OF XATURSL
132
PRODUCTS
[VOL.
44,
NO.
TABLE 1. Continued. Constituent Alkaloids
Plant
L . tschimganica Myosotis syloafica Hoffm.. , . .
.
....
Paracynoglossunt znieritzn~rniKusn. M. Pop
Rindera airstroechanata 11.Pop R . baldschzranzca Kusnezov
R. cyclodonta Bge R. echanata Regel R. oblongafolaa 1.1.Pop Solenanthus czrcznnatus Ledeb. S . coronatus S.karategenius Lipsky
S turkestanzczrs Regel e t Smirnov S3mphytuni asperuin Lepech.
S. caucasicum..
,
.
..
S.o j i c i n a l e . . . . . . . . . .
S.orienlale S . tzrberosum S . x uplandzcuni Nyman
carategine echinatine viridiflorine viridiflorine 9-angelylretronecine heliosupine acetplheliosupine heliosupine echinat ine echinatine rinderine echinatine trachelanthamine turkest anine echinatine echinat ine t rachelanthamine carategine echinatine turkestanine echinat ine echinatine carategine echinatine rinderine turkestanine asperumine :chinatine heliosupine 7-acety11ycopsamine (or diastereoisomer) acetylechimidine (or diastereoisomer) lasiocarpine asperumine echinatine echimidine symph y t ine :chimidine lasiocarpine heliosupine viridiflorine :chinat ine 7-acetyllycopsamine (or diastereoisomer) 7-angelylretronecine viridiflorate (or diastereoisomer) acetylechimidine (or diastereoisomer) anadoline symphytine echimidine echimidine anadoline symphytine symlandine echimidine 7-acet yllycopsamine 7-acetylintermedine uplandicine 1ycopsamine intermedine
Plant Part
Ref.
ae
87
wh
35
88 89, 90 If, st, sd, r t 87 91 ae 87 ae ae, rt
ae ae ae ae
59 92 59 87
sd, ae, rt ae ae
93 75 93
ae
94
ae, rt ae, r t
95, 96 97
wh
31
ae, rt ae, rt
95 98, 99
rt se, rt le, rt rt rt wh
15, 16 100 95 101 31
wh
102, 103, 104
wh
105
Be
31, 17, 106
2
?JAR-APR
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S V I T H A S D CCLVESOR
133
PYRROLIZIDISE ALKALOIDS
TABLE 1. Continued. Plant
Constituent Alkaloids
Tournefortia sarnienfosn Lam. Trichodesnia ajricana . . . . . . .
T . incanum Alph. D C . T . zeylonicirni (Burm. f . ) 11. B r . , . . . . Ulegbekia tschiniganica (B. Fedtsch.)
supinine europine intermedine richodesmine incanine supinine
~
Plant Part
If, s t wh
107 419
ae sd, ae, r t sd
108, 109 110, 111, 112 113
Zak.. . . . . . . . . . . . . . . . . . . . uluganine
111
COMPOSITAE ildenosiyles alliuriue, . . . . . . . . . . platyphylline seneciphylline " d d e n o s t j l e s rhonibifolia (Wil1d.j >I. Pimen. ssp. p l a i y p i i y l l o i d e s . . . . platyphylline seneciphylline Brachygloitis repanda Forst. et Forst., . . . . . . . . . . . . . . . . . . . senecionine senkirkine brachyglot t ine Cncalia floridaiia o t osenine florosenine floridanine floricaline C. i i a s t ~ t aL. subsp. orieiitalis Kitamura.. . . . . . . . . in t e ge rr,im,ine yamatalmine C. yatabei Maxim.. . . . . . . . otosenine Doronicicni inacropiiyllitni. . . . floridanine doronine Enrilia .ffaniineu Cass. otosenine emiline E . sonchifolia DC. senecionine Erechti!es hieracifolin (L.) Raf. ez DC. . . . . . . . senecionine seneciph ylline E . qnudrideniaiu (see Senecio qziudridenta tus Labill. ) E u p a t o r i u m cnnnnbinuni L. echjnatine supinine echinat ine E . niaculaircni L. .... t rachelanthamidiiie probably echinatine E . purpicrezcin ..... supmine E . serotinunz hlichx.. . . . rinderine E . sfoerhndosmunz Hance linde1:fine supinine Furjugiuni jriponicion. . . . senkirkine Ligularia bmchyph$lii Hand.-RIazz., clivorine lignlarine ligudentine L . clivor~cni clivorine ,
L . dentaiu ( A . Gray) Hara
clivorine ligularine ligudentine ligularidine
Ref.
rt
115
ae
11G
ae
117
ae
118 119
rt rt rt
120 121 122
ae, rt
123, 124, 125
ae
35
ae
126, 127
ae
128
rt
129
ae ae
130 131
rt
132
rt, If ae
133 134
ae
135, 136, 137, 138 134
ae rt,
ae
136
aPimenov ei i l l . (116) have given the name Adenosiyles riioinbifoliits to the species which have previously been known as Senecio ploijphyllirs, S . p l ~ i t y p h v l l o i d e s ,and S . rhonibifoliits (251, 208). They have divided the species into two subspecies, one of which is further divided into two cheniovariants, each with different alkaloidal content. Since plant material esaniined in earlier publications cannot be related to the classification of Pinienov et i t l . , each alkaloidal isolation is listed under the species name by which it was originally published.
JOURKAL OF SATURAL PRODUCTS
134
[VOL.
44, so. 2
TABLE 1. Continued. Plant
Constituent Alkaloids
L . elegans (Cass.) (syn L . niacrophylla (Ledeb. DC.)) Naardosmia luevigata (Willd.) DC. (see Petasites laevigatics (Willd.1 Reichenb.) Petasites hybridus (L.) P. Gaertn. et al.. . . . .. . ..... . . . . P . japonicics Maxim.. . ... . . , ,
,
,
P . laee~ign!its(Willd.) Reichenb. Senecio aegypticiis L.
S . a l p i n u s (L.) Scop.. . . . . . . . . S . ambrosioides. . . .
.
.
. . .. .. . .
S.ampullaceus Hook. S. antieuphorhiuni (L.) Sch. Bip. . . .
S . aquaticus Hill. . . . . S. aureus L . . . . . . . . . , . . S. aicricola Bourg. S. bipinnatisecfus Belcher. . . S. borysthenicus. . . . . . . . . . . . S . brasiliensis DC.. . . . . . . . . .
S. bupleurotdes DC S. cannabafolaiis Less S.carthamoides Greene
S . chrysanthemoides S . cineraria D C .
S.cruentics DC S . cymbalaraozdes S. dehfontaznez Druce
S . discolor DC.. , . .
.
. .
S . doronicum L . . . . . . . . . . . . . .
. .
Plant Part
Ref.
clivorine ligularine ligudentine
ae
134
senecionine fukinotoxin (petasitenine, neopetasitenine senkirkine petasinine petasinoside platyphylline senkifkine (renardine) senec!on!ne senecionine o t osenine riddelliine senec lphylline jacozine senecjphylline senecionine ret rorsine ridde!liine senecionine seneciphylline ret rorsine intcgerrimine senkirkine senaetnin isosenaetnin seneciphylline senecionine neosenkirkine ret rorsine senec jphylline senecionine seniciph ylline jacobine integerrimine ret rorsjne retrorsine seneciphylline senecionine seneciphylline seneciphylline jacobine senecionine seneciphylline ot osenine ret rorsine cruentine A cruentine B senec!on!ne senecionine o t osenine riddelliine seneciphylline retrorsine senecionine doronenine bulgarsenine
If ae
35 20, 19, 139
st ae
140 141
ae ae
142 143, 144
wh
145, 146
ae
147
wh
148
nh
420 149, 150, 151
ae
152
le
421
ie ie le ie, r t le, rt f
153. 155; 157 158 159, 161. 148;
154 156 160 162 163
ie ie ie Kh
ie jd Le ie ie
164 165 149, 151 166 153, 167 168 169 170 171 172
ie
420 173, 145
ie f ie rh
146 174 175 176
lIAR-APR
19811
SMITH A S D CULVESOR
135
PYRROLIZIDISE ALKALOIDS
T ~ B L1.E Continued.
,
Plant
I I
S. douglasii D C .
Constituent Alkaloids
Plant Part
retrorsine riddelliine senec jphylline senerionine integerrimine senecionine seneciphylline retrorsine riddelliine senecionine ot osenine floridanine
S.d i t r i e i i i Gay. S.ereniophilus Richards
S.erruficits Berthol.
Kef.
wh
149, 150, 151
nh ~ 5h-
157 149, 150, 151
ae
177
ae
178, 179, 180
If ae ae ae
181 182 153 183, 180
ae ae
184 185
ae
18G
nh
148
wh ae ae
187 153 188
ab'
189
S.erratzcits Berthol. subsp. barbnraeifoliiis Krock
S.eritc~'joliits L . . .
. . . . . . . .
S.$iwi.~filisWallr..
.
.
.I
.
~
~
S.foriwosirs,
.
.
.
S.frenioiiii Torr. et -1.G.ray .
'
S.fztchsii K . C. Gmel. (see S.
nenioreiisis L . ssp. fztchsii Gnielin) S. glnbelliis (Turcz.) D C . . . s.glaberriniirs D C . , . . S. grai?:inifoliirs ?;. J. J a c q . . .
S.g r a n d i f o l i o . . S.griesebachii.
. . . . . . . S. ilicifoliirs T h u n b . . . . . . . . . . . .
S.incoilits L. subsp. c~irniolicirs (Willd.) Br.. . . . . . . . . .
S.infegerriniirs S u t t . . . S.isiiiideits D C . . S.jocobaea L . . . .
.
.
S.k i r k i i Hook. f . es Kirk S . kleinia Sch. Bip., S . krylor,ii.. . . .
,
,
. .
~
senecionine otosenine erucifoline seneciphylline integerrimine senecionine seneciphylline erucifoline (base S-C) retrorsine seneciphylline otosenine florosenine, integerrimine retroSsine senecionine seneciphylline senecionine retrorsjne retrorsine graminifoline platyphylline seneciphylline retrorsine senecionine
I
~
ae
190 191, 192, 188, 127
ae ae
147 150
If,
St
seneciphylline retrorsine seneciphyl!ine integerrimine senecionine plat yph ylline neoplatjphylline retrorsine senecjphylline senecionine jacobine jaconine jacoline jacozine otosenine senkirkine retrorsine senkirkine 0-acet ylsenkirkine integerrimine senkirkine seneciph? lline
I
420 ae ae
153, 193 194, 195 196, 167 153, 197, 198, 199. 200. 201. 202' ' '
' ae
51
ae
184 203 204 205 206 207
~
bk, If If st
st I ae
JOUHKAL OF SATURAL PRODUCTS
136
[VOL.
44,so. 2
TAULE 1. Continued. Plant
Constituent Alkaloids
S . kubensis Grossh.. . ... . S . lanzpsanoides., . . . . . . . . . . . , s. lntifoli1ts n c . . . . . . ... . ,
S. laibfits Forst. f . . . . S . longilobiis Benth.. . .
. . .,.. . . ,...
,
S. nzugn$cits F. hluell.. . . .
S.minimus Poir. . S.niorrisonensis H a y a t a . .
.
.
.
.. .
S. nebrodensis L. var. sicrilci. .
S.nenzorensis L. v a r biilgaric1is (S-el Stoj. e t Stef.. . . . . . . . . . . . . . . . S.irenzorensis L . var sirbdeczirrens Griseb. , . . . . . . . .
,
, ,
.,
.
. .
. ..
S.neniorensis L. sap. fzichsii Gmelin.. . . . . . . . . . . ,
,
S . othonnae Bieb.
S . oiboizn307 (1969). 153. J. J . Blackie, PIinrn7. J . , 138, 102 (1937). 154. W .C. Evans and E . T. R . Evans, -1-oture ( L o n d o n ) ,164, 30 (1949). 155. R.H . F. llanske, Cun. J . Res., Sect. B . , 14, 6 (1936). 156. R.H. F. Llanske, Con. J . Res.: Sect. E . , 17, 1 (1939). 157. F. 11.Panizo and B. Rodriguez, -477. Qiiini., 70, 1043 (19i-k). 158. E. P. K h i t e , -Y.Z . J . Sci.. 12, 165 11969). 159. .1.L. Red'ko, S e k o t o r y e T'opr. F i i r v i , : Sb. -\-oiichn, T r . Tvyss/i. Furni. 1-cheb. Znxdenii I l r . S.SR. 103 11956): Chen7. . l b s f r . , 53! 2C695h (19591. 160. 1.. S..Ilekseev, .lfed. Proi~:-s?.S S S R , 15 111), 27 (1901): C h e m . d b s i r . , 57, 7384i 11962). 161. .\. Sovelli and A . P. G .de T.arela, &An,.Asoc. Qtrim. A r g e n t . , 33, 176 il94.5): Chem. A b s i r . , 41, 2418c (1947). I
,
I
I
;
148
JOURKALO F
NATURAL PRODUCTS
[VOL.
44, s o . 2
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~
JihR-.4PR
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SJIITH A S D CULVESOR
:
PYRROLIZIDISE ALK.4LOIDS
151
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378. 379. 380. 381. 382
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