International Journal of Analytical Mass Spectrometry and Chromatography, 2013, 1, 109-118
Published Online December 2013 (http://www.scirp.org/journal/ijamsc)
http://dx.doi.org/10.4236/ijamsc.2013.12014
Open Access IJAMSC
Structure Elucidation of a New Toxin from the Mushroom
Cortinarius rubellus Using Gas Chromatography-Mass
Spectrometry (GC-MS)
Ilia Brondz1,2
1Department of Biosciences, University of Oslo, Oslo, Norway
2R & D Department of Jupiter Ltd., Ski, Norway
Received October 28, 2013; revised November 24, 2013; accepted December 27, 2013
Copyright © 2013 Ilia Brondz. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Cortinarius orellanus (Fries) and C. rubellus (Cooke), which were formerly also known as C. speciosissimus, are poi-
sonous mushrooms containing the toxin orellanine and several degradation products of orellanine, including orelline
and orellinine. Mass intoxication by poisonous mushrooms was observed in Poland in 1952-1957 [1]. In 1957, the cause
of these outbreaks was described by Grzymala as poisoning by a member of the Cortinarius family. The toxin
orellanine was first isolated from C. orellanus by Grzymala in 1962; the chemical structure of orellanine was later de-
termined to be 3,3,4,4-tetrahydroxy -2,2-bipyridine-N,N-dioxide. Poisoning with C. orellanus and C. rubellus has a
very specific character. The first symptoms of intoxication usually do not appear until 2 - 3 days after ingestion, but in
some cases intoxication appears after three weeks. The target organ for the toxin is the kidney. Histologically, it is easy
to record the specific damage. The presence of degradation products of orellanine in kidney can be confirmed chro-
matographically, suggesting that the cause of poisoning is orellanine. However, the presence of orellanine in the blood
of intoxicated persons has not been directly detected. A specific model was developed by Brondz et al. for the detection
of orellanine, orelline, and orellinine in animal stomach fluids [2-4]. The hypothesis that the fungal toxin orellanine as a
diglucoside can be transported from the digestive system by the blood to the kidney could not be supported. The toxin
orellanine as a diglucoside is very unstable in an aqueous acidic environment. However, in the present study, it was
possible to record an additional substance in animal stomach fluids using GC-MS after ingestion of C. rubellus. This
substance, which has been named rubelline, is part of a toxic mixture in C. orellanus and C. rubellus and is closely re-
lated to orellanine. The structure of rubelline is more suitable than orellanine for absorption from the digestive tract and
for transport in the blood. The presented hypothesis is that rubelline is absorbed in the digestive tract and transported in
the blood to the kidney, where it is biotransformed to orellanine and accumulated to toxic levels. The process of bio-
transformation is in itself also damaging for the kidney and liver. GC-MS instrumentation enables the separation of sub-
stances in biological samples and in the extract from C. rubellus. The GC-MS with SMB technique was used to record
the mass ion and to record a detailed fragmentation picture.
Keywords: Gas Chromatography; Mass Spectrometry
1. Introduction
Humankind has known poisoning by toxic mushrooms
from the early stages of civilization. The attraction of
mushrooms as delicious nutritious food has been known
to humanoids starting from humanoid apes. Nonbotanical
grouping simply classifies mushrooms as edible, nonedi-
ble, and toxic [5]. In the Roman Empire, toxic mush-
rooms became a political tool and were used for the as-
sassination of highly ranked politicians including some
imperators. Mithradates VI (Greek: άς), King
of Pontus was known for his extensive use of toxic
mushrooms for poisoning and as an antidote [5]. In the
Roman Empire, the slave-cooks were obliged to eat
meals containing mushrooms one day ahead of an imper-
ator—if the slave-cook was well one day after, the meal
was served to the imperator. However, even this precau-
tion could not save the life of the imperator if C. orella-

I. BRONDZ 110
nus or C. rubellus was laid on the table as a part of the
meal, because the latent period between ingestion of
these mushrooms and the appearance of the first symp-
toms of poisoning can stretch up to two or three weeks
[2-6].
Intoxication by C. orellanus or C. rubellus is charac-
terized by a loss of kidney function, the so-called
“orellanus syndrome” with an extremely long-latent pe-
riod of up to three weeks [2-6] before renal failure, and
often extending to severe renal damage and the need for
dialysis, or even to death as a result. Presently, the sig-
nificance of ingestion of small doses of these toxic
mushrooms is not clear, especially if the quantity of in-
gested toxin does not exceed toxic levels, but is repeated
within short intervals (in one or two days), or within long
intervals (in weeks or months). Will the kidney recover
from intoxication or will there be a long-term impairment,
for example for months or years? Will the damage be
repaired in the long term or will repetitive ingestion of
small doses, even over long intervals, lead to cumulative
effects and result in kidney function failure or even death?
These are not only academic questions, but also more
practical ones because debris of C. orellanus or C. ru-
bellus can appear in the mixtures of “forest mushrooms”
prepared and sold commercially. The appearance of an
increased number of patients with kidney failure can be
explained by these intoxications or by intoxications with
pesticides such as paraquat and diquat, which are similar
in chemical formula and in their picture of intoxication.
Different toxins are blamed for the intoxication by C.
orellanus or C. rubellus; for example, the cortinarines [7].
However, structures of cortinarines as described by Teb-
bett and Caddy [7] have been criticized by Matthies and
Laatsch [8]. The existence of so-called cortinarines is
highly questionable; thus, intoxication by cortinarines is
also questionable. However, one hypothesis that persists
is that the responsible poisonous substance is orellanine
and partly its degradation products (Figure 1).
However, to our knowledge, there is no published lit-
erature that describes the presence of orellanine in blood
samples after cases of intoxication by C. orellanus or C.
rubellus. The description of the presence of orellanine in
kidney after a case of intoxication by C. orellanus or C.
rubellus is given by using thin layer chromatography
(TLC) [9], in which Rohrmoser et al. stated: “Orellanine
can be detected after a relatively long period following
poisoning by performing a simple thin layer chromatog-
raphy technique using small quantities of renal biopsy
material. No toxin was found in urine or blood samples.”
In another report, the presence of orellanine was estab-
lished indirectly: “By assaying orellanine in the plasma
and two renal biopsies of patient after specific photo-
decomposition into a non-toxic metabolite called orel-
line” [10]. This indirect determination of orellanine by
using an evidence of the presence of its degradation
product orelline has several weaknesses.
1) Quantitative determination was not supported by
dynamic and quantitative determination of output from
the performed reaction.
2) There is no evidence that a substance other than
orellanine was not a source for the resulting product
“orelline” in these experiments.
3) There is no evidence that the orelline was absent in
the blood before the so-called “degradation reaction by
irradiation”. In other words, the orelline could have come
directly from the mushrooms themselves. The orelline
may be present in the mushroom basidiocarps as a sec-
ondary metabolite and as a degradation product of orella-
nine. This issue is the greatest weakness in the study.
4) The argument that the orelline resulted entirely
from the photodegradation reaction is not supported in
[10] and cannot be supported by this way.
Antkowiak et al. described the chemical structure of
orellanine as 3,3,4,4-tetrahydroxy-2,2-bipyr idin e- N,N-
dioxide [11]; later, Holmdahl et al. supported the authen-
ticity of this chemical structure by 1H-NMR and 13C-
NMR spectra analyses [12].
The presence of orellanine in the mushrooms as a di-
glucoside was described in [13]; however, the NMR
spectrum described here was not in good agreement with
the theoretically calculated spectrum described in [4].
In [14], Herrman et al. supported the existence of
orellanine Figure 2 as diglucopyranoside and suggested
that orellanine-4,4-diglucopyranoside is unstable in an
aqueous acidic environment.
This can explain the inability to detect orellanine-4,
4-diglucopyranoside in stomach fluids in experiments
described in [2-4]. In the present study, a more careful
approach to analyses of stomach fluids was taken by op-
timizing gas chromatography-mass spectrometry (GC-
MS) with supersonic molecular beams (SMB). Basidio-
carps from C. rubellus were examined for the presence of
a new toxin/s. The priority was to detect the substance/s
that could be present in stomach fluid as a result of di-
gestion of C. rubellus and that could be absorbed and
transported in the blood to the kidney. It has been shown
[14-16] that semisynthetic thermolabile heterocyclic sub-
stances can be successfully analyzed by using GC-MS
with SMB techniques. By comparison with conventional
GC-MS, the temperature of the analyses in GC-MS with
SMB is significantly lower, the time of a single analysis
is shorter, the gas flow in the capillary column is higher,
and a contact-free fly-through EI ion source technique
prevents contamination. The GC-MS with SMB tech-
nique was used to record the mass ion and to record a
detailed fragmentation picture. All these advantages
were used for tentative elucidation of the structure of
rubelline.
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I. BRONDZ
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111
Figure 1. The poisonous substances in Cortinarius orellanus and C. rubellus are orellanine structures 1 and 4, and the degra-
dation products orellinine structure 2 and orelline structure 3.
Figure 2. The structure of orellanine diglucopyranoside as
presented in [13].
2. Materials and Methods
2.1. Biological Material, Standards, and Extracts
for Biological Testing
Mushrooms C. rubellus were kindly provided by Jupiter
Ltd., Norway and freeze-dried to a constant weight as
described in [4]. The procedure for extraction and isola-
tion of their toxins was conducted as described in [17].
The orellanine standards were donated by Jupiter Ltd.,
Norway. Cells of Chlamydomonas reinhardtii were pre-
pared as previously described in detail [18,19].
2.2. Biological Testing of Toxicity
The test model used in the experiment was as previously
described [18,19].
2.3. Instrumentation and Conditions
GC-MS instrumentation enabling the separation of sub-
stances in biological samples and in the extract from C.
rubellus is described in detail in [16]. The extracted sub-
stances were dissolved in methanol p.a. quality (Merck,
Darmstadt, Germany). The capillary column used was an
Rxi-5Sil MS low polarity phase; Crossbond 1,4-bis (di-
methylsiloxy) phenylene dimethyl polysiloxane catalog
no. 13620, 15 m, ID 0.25 mm, film thickness 0.25 m
(Restek, Bellefonte, PA, USA). The column was reduced
to about 4.5 m in laboratory. The helium column flow
rate was 8 mL/min. Samples (1 L) at an approximate
concentration of 20 ppm of dry mass were injected with a
split ratio of 10:1 using a Varian 1079 injector operated
at 150˚C. The GC oven was programmed from 130˚C to
330˚C at 20˚C/min.
Ion source degradation was prevented by virtue of a
contact-free fly-through EI ion source [16], and degrada-
tion of substances in the sample was further avoided be-
cause of the use of a short column and a high gas flow
rate.
The MS instrument was operated in an electron impact
(EI) mode at 70 eV. The mass spectra between m/z 50
and m/z 700 were obtained at a scan speed of 200 m/z
unit scan/s with a mass resolution corresponding to 1 unit
at half peak height. Separation and detection of sub-
stances in the stomach of Mus rattus L. are shown in the

I. BRONDZ 112
reconstructed ion chromatogram (RIC) in Figure 3 and
the substances isolated directly from C. rubellus in Fig-
ure 4. The mass spectra of substances shown in Figure 3
are shown in Figures 5-8 .
3. Results and Discussion
3.1. Biological Testing of Toxicity
The toxicological test is described in [18,19]. The thres-
hold concentration of dry substance rubelline from C.
rubellus used for inhibition of growth of Chlamydomo-
nas reinhardtii cells was 10 ppm. Only qualitative results
were recorded. Cell movement was abolished after ex-
posure to the extract. This abolition of cell movement
was the result of flagella blockage [20]; the authors of [20]
noted: “The evidence is strongest for a role in triggering
the shedding of flagella by the unicellular alga Chlamy-
domonas reinhardtii under acid stress. Rapid kinetic
Figure 3. An RIC of the analyzed stomach fluid is shown: peak A is rubelline, peak B is orelline, peak C is orellinine, and
peak D is orellanine.
Figure 4. An RIC of the rubelline.
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I. BRONDZ 113
Figure 5. Mass spectrum of rubelline.
Figure 6. Mass spectrum of orellanine.
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I. BRONDZ 114
Figure 7. Mass spectrum of orelline.
Figure 8. Mass spectrum of orellinine.
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115
analysis indicates that phosphoinositide hydrolysis oc-
curs within half a second and could trigger the rapid loss
of flagella.” Most of the cells lost their chlorophyll and
the cell lysis began as a result of exposure to the toxin.
Figure 1 presents orellanine and its degradation prod-
ucts. Degradation of orellanine occurs in the bodies of
intoxicated persons and other organisms after ingestion
of the mushrooms, in the basidiocarps of the mushrooms
themselves, and during extraction.
The diglucoside of orellanine is an unstable substance
(Figure 2) and degrades to the monoglucoside and
orellanine itself [13,14]. The diglucoside of orellanine is
particularly unstable in aqueous solutions at acidic pH
[14] and this is probably the reason that it was not de-
tected in experiments described in [2-4]. However, if the
molecular structure exists, there is little chance that it
will be absorbed and transferred into the blood stream
because of its extreme instability in the aqueous acidic
conditions [14] in the stomach.
3.2. Analysis of Stomach Fluid from Mus rattus L.
The time of digestion of a meal containing C. rubellus in
the stomach of the mouse Mus rattus L. was reduced to 1
h. The injector temperature in GC was set at 150˚C (low
by comparison with previous analyses) to minimize the
degradation at the injector. The VF-5HT column, I.D.
0.25 mm, film thickness 0.1 m, and 4 m length (Varian,
Middelburg, The Netherlands) was changed to an Rxi-
5Sil MS low polarity phase; Crossbond 1,4-bis (dime-
thylsiloxy) phenylene dimethyl polysiloxane, catalog no.
13620.15 m, I.D. 0.25 mm, film thickness 0.25 m
(Restek) column, which was reduced in length to about
4.5 m in the laboratory. A high flow rate in the capillary
was used to reduce the time of analysis and avoid degra-
dation of the analytes.
An RIC of stomach fluid from Mus rattus L. is shown
in Figure 3.
An RIC of authentic rubelline donated by Jupiter Ltd.
is shown in Figure 4.
The retention time for the peak A in the chromatogram
in Figure 3 is the same as the retention time of standard
in Figure 4. The mass spectrum shown in Figure 5 is the
mass spectrum of peak A shown in Figure 3 and it is
similar to the mass spectrum derived from the standard
shown in Figure 4.
The m/z of rubelline is 4 units greater than the m/z of
orellanine eluted under peak D; the mass spectrum of the
substance eluted under peak D is shown in Figure 6.
The mass spectrum shown in Figure 6 is characteristic
of orellanine.
The substance eluted under peak B yielded the mass
spectrum shown in Figure 7.
The substance eluted under peak C has the mass spec-
trum shown in Figure 8.
It appears as if the sequence of elution progresses from
less polar and lower boiling substances to more polar and
higher boiling substances as shown in Table 1. This was
expected using the Rxi-5Sil column for GC-MS analyses.
The toxicity from orelline to orellanine progressed from
the low-molecular-weight orelline as nontoxic to the
higher-molecular-weight orellanine as the most toxic in
the sequence. Because of this, it is expected that rubelline,
with the highest molecular weight, is most toxic, as was
described for trivalent heterocyclic nitrogen and penta-
valent nitrogen alkaloids [21,22]. The hypothesis is: the
toxicity from orelline to rubelline should progress from
the low-molecular-weight orelline as nontoxic to the
higher-molecular-weight rubelline as the most toxic in
the sequence.
Examples of biological transformation of less polar
alkaloids to polar-charged molecules are known. These
polar-charged molecules have a higher boiling point. An
example of this is the transformation of (S)-canadine to
berberine Figure 9.
The tentatively elucidated structural formula for rubel-
line is shown in Figure 10.
Orellanine and rubelline are similar and they are re-
lated structurally to paraquat and diquat. Paraquat and
diquat are nonselective bipyridyl herbicides; rubelline
exhibits the herbicide cytotoxic effect. As stated by Jones
and Vale [23] “Diquat is a potent redox cycler and is
readily converted to a free radical which, in reaction
with molecular o xygen, generates superoxide anions and
subsequently other redox products. These products can
induce lipid peroxidation in cell membranes, and poten-
tially cause cell death.” The cytotoxic effect of rubelline
was tested in a specific model [19] on unicellular algae
Chlamydomonas reinhardtii. The model was developed
to test the ability of primaquine and quinocide to inter-
fere with the electron transport chain, to scavenge elec-
trons, and to produce peroxides and radicals in the living
cell.
4. Conclusions
1) The molecular weight of rubelline is 256 and the
structure of rubelline was tentatively elucidated using
GC-MS.
2) Rubelline is less polar than orellanine and is conse-
quently more suitable for absorption in the stomach and
digestive tract and transport in the blood to reach target
organs such as the liver and the kidneys.
3) Rubelline is converted in mitochondria to orellanine
and gradually concentrates in the kidney.
4) The biotransformation of rubelline to orellanine
impairs kidney function by interference with electron
transport, by production of radicals and peroxides, and

I. BRONDZ 116
Table 1. The characteristics for: rubelline, orelline, orellinine and orellanine.
Peak A B C D
Rubelline: CAS No. Orelline: CAS No: 72016-31-0 Orellinine: CAS No.: 98726-96-6Orellanine: CAS No.: 37338-80-0
Molecular Weight: 256.1 Molecular Weight: 220.1815 Molecular Weight:236.1809 Molecular Weight:252.17
Boiling Point: not known Boiling Point: 257.4˚C at 760 mm HgBoiling Point: 282˚C at 760 mm HgBoiling Point: 834.615˚C at 760 mm Hg
Formula: C10H12N2O6 Formula:C10H8N2O4 Formula: C10H8N2O5 Formula: C10H8N2O6
Retention time
Rubelline Orelline Orellinine Orellanine
5.38 min 5.84 min 6.92 min 8.05 min
Figure 9. The transformation of (S)-canadine to berberine.
by direct toxicity.
5) Orellanine is a toxic substance that gradually con-
centrates in the target organs until the concentration be-
comes such that critical irreversible damage occurs.
6) The process of biotransformation from rubelline to
orellanine takes time and this may explain the long-latent
period of Cortinarius poisoning. Individual differences in
enzyme activity in different patients may explain the
difference in the latent period: in some patients this is 2
days, in others up to 3 weeks.
7) The discovery of a molecule with m/z 256 suggests
that a molecule with m/z 580 may exist. A hypothetical
molecule with m/z 580 should have the structure shown
in Figure 11.
5. Acknowledgements
The author is grateful to Jupiter Ltd., Norway, for finan-
cial support, biologic material and standards, to Professor
Aviv Amirav, School of Chemistry, Tel Aviv University,
Tel Aviv, Israel for technical assistance with gas chro-
matography-mass spectrometry and to Anton Brondz,
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I. BRONDZ 117
Figure 10. The possible biotransformation of rubelline to
orellanine.
Figure 11. The hypothetical molecule with m/z 580 possibly
can be found in C. orellanus or C. rubellus.
Department of Chemistry, Norwegian University of Sci-
ence and Technology, Trondheim, Norway, for the pre-
paration of the figures.
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