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[CANCER RESEARCH 35, 3693-3697 December 1975]
Synthetic and Naturally Occurring Hydrazines as Possible Cancer
Causative Agents
Bela Toth'
The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105
SYNTHETIC
SUMMARY
The various synthetic
substituted
hydrazines,
which cause
tumors in animals, are briefly enumerated. To date, 19 of
them have proved to be tumorigenic in animals. A number
of these chemicals are found today in the environment, in
industry, in agriculture, and in medicine, and the human
population is exposed to a certain degree to some of them.
Hydrazine
also occurs
in nature
in tobacco
and tobacco
smoke. The three other naturally occurring hydrazine
compounds
are N-methyl-N-formylhydrazine,
which oc
curs in the wild edible mushroom, Gyromitra esculenta,
and
@-N-[―y-L(+)-glutamylJ-4-hydroxymethylphenyl
hydrazine
and 4-hydroxymethylphenylhydrazine,
whkh
are found in the commonly eaten cultivated mushroom,
Agaricus bisporus. Tumorigenesis
studies with the natu
rally occurring
hydrazines
are in progress.
Interest in chemical carcinogenesis
in the past few
decades has focused on the possible roles of synthetic
chemicals that may cause cancer in man. This appeared
justifiable on the. grounds of recent estimates that approxi
mately 200,000 new chemicals enter our environment each
year. If only 1% of these chemicals enter at reasonably high
levels, this means that man may be exposed to around 2,000
new chemicals annually. To date, around 6,000 chemicals
have been studied for carcinogenic
activities; of these,
approximately
1,000 compounds have thus far been found
to be tumorigenic in animals. According to some experts,
the exogenous hazardous agents are to a large extent
responsible for the cancer incidence in the human popula
tion.
The aim of this report is to draw attention
and naturally
occurring
derivatives
to both the
of hydrazine.
The synthetic hydrazines in recent years were shown to
produce tumors in animals, and therefore they may play a
role in the etiology of human cancer. With the exception of
hydrazine itself, the other naturally occurring derivatives of
this compound,
tumor-inducing
however, have thus far not been studied for
abilities.
aRecipient
of USPHS
Research Career Development
K04-42,552 from the National Cancer Institute.
Received June 5, 1975; accepted August 26, 1975.
DECEMBER
Studies on the carcinogenic potentialities
of synthetic
substituted hydrazines began in 1962, when it was shown
that the base compound hydrazine sulfate induced lung
neoplasms in mice (1). Subsequently, a series of hydrazine
derivatives were investigated in various laboratories
for
tumor-inducing
capabilities. These studies clearly demon
strated that these chemicals are indeed powerful tumori
genic substances in mice, hamsters, and rats, due to their
tumor-inducing
abilities in the intestines, brain, lungs,
blood vessels, liver, breasts, kidneys, etc. Now, we know of
19 hydrazine
Award
derivatives
that have been shown to be tumor
inducers. These include, in addition to hydrazine (1, 32),
methyl- (35, 40), 1,2-dimethyl- (6, 27, 36, 46, 52), 1,1dimethyl- (28, 37), benzoyl- (2, 34), phenyl- (2), 2-hydrox
yethyl- (I I), 1,2-diethyl- (5), l-acetyl-2-isonicotinoyl(39)
hydrazines;
INTRODUCTION
synthetic
HYDRAZINES
N-isopropyl-a-
(2-methythydrazino)-p-tolua
mide (13, 14); and l-isonicotinoyl-2-isopropyl(2), or
thometoxybenzoyl(2), paramethoxybenzoyl(2), 1-meth
yl-2-butyl- (4), l-methyl-2-benzyl(4), ethyl- (42, 44),
n-butyl- (44), 1-carbamyl-2-phenyl(4 1), carbamyl- (43),
and n-amyl- (33, 38) hydrazines. Their names, chemical
structures,
treatments,
and action sites are summarized
in
Table 1.
These studies received particular attention because syn
thetic hydrazines are present in the environment and are
used in industry, agriculture, and medicine. They include
hydrazine,
monomethylhydrazine,
and 1, l-dimethylhydra
zinc, which are components of rocket fuels (26); carbamyl
hydrazine, an industrial and laboratory reagent (26); 2hydroxyethylhydrazine,
a ripener for pineapple and other
plants (10); phenylhydrazine,
used in treatment of polycy
themia vera (26); 1-isonicotinoyl-2-isopropylhydrazine,
an
antidepressant
and antituberculotic
drug (3 1, 53); and
N-isopropyl-a-(2-methylhydrazino)-p-toluamide,
an an
tineoplastic agent (25). To what extent humans are exposed
to the industrial hydrazines is presently not known. We do
not even have data concerning whether or not the pineapple
fruit contains the ripening agent. The amounts of these
various hydrazines used as therapeutic drugs are known and
they are not administered, however, on massive scales.
The fact should be also emphasized that all hydrazine
derivatives
studied
in laboratory
altogether) to be tumor-producing
animals
were found (19
substances. It is esti
1975
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3693
B. Toth
Table I
Tumorigenic hydrazine compounds
Compound
Species
Organ
Treatment
References
c0N14-*4C0c143
MiceLungsp.o.39MiceLungs,
1-k,TyL-2-,,olucoyn.oyu,vz*,z,.i
CH,—CH,—CH,---CH,—CH,—NH—NH,
N-Amylhydrazine
HCI
K@N@*2
vesselsp.o.33P.O.2,34p.o.44P.O.43p.o.41s.c.5p.o.28,37Mice
blood
Mice
Lungs, lymphoreticular
tissue
NH,—NH—CH2—CH,—CH2—CH,.
N Butylhydrazine HC1
Mice
Lungs
NH,—NH---CO—NH2.
HCI
Carbamylhydrazine
. HCI
M ice
Lungs, blood vessels
Mice
Lungs
Rats
Lymphoreticular
kIIZOYUIYDIAZIII
CH,—CH,—NH—NH—CH2—CH1
1,2-Diethylhydrazine•
and
nerve
tissues,liver,ethmotur
binal
(CH1), N—NH,
1.1-Dimethyihydrazine
CH,—NH—NH—CH,
1,2-Dimethyihydrazine
. 2HC1
Mice
Lungs. blood vessels, kidney,
liver
Colon, lungs, blood vessels
27,36Ratss.c.,
Hamsterss.c., Liver, stomach, intestine,
p.o.
i.m.,p.o.46,
52
bloodvessels
Intestine
p.o.6Micep.o.42Mice
NH,—NH—CH,—CH,.
Ethylhydrazine . HCI
NH,—NH,. H,SO4
Hydrazine sulfate
Lungs, blood vessels
liver
RatsLungs, Liver, lungsp.o.
32MiceLiverp.o.11MiceLungsp.o.2Mice
p.o.1
NH,—NH—CH,—CH,OH
2-Hydroxyethythydrazine
1I$ONICOTIIOYI.2IIOPIOPYU4YDMZI@(
QCr*-IC-012
@J
co@NI1
N-Isopio@vi-d-(2-ICTwyi.syDI*zIuo)P-TO@uMIX
CCI
lymphoreticular
tissue, kidney
14MiceLungsp.o.2MiceLungsp.o.2Mice
RatsLungs, Breast, lungs, blood
i.p.
p.o., i.p.13
vesselsp.o.,
2043
O-@ThOXYIINZOYUIYDIAZINI
0I@0
P—@THOXYWIZOYLHYDIAZINt
CH,—NH—NH,
Methylhydrazine
3694
HamstersLungsKupffer cells, cecump.o.
p.o.35
40
CANCER RESEARCH VOL. 35
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Hydrazines
and Cancer
Table I—Continued
CompoundSpeciesOrganTreatmentReferencesCH3-NN-mC-CH2
@
p.o.4CH,—NH—NH—CH,—CH,—CH,—CH,.2HCI
and peripheral ncr
vous systems, bulbus ol
14@T)ffL2UNZYUIYDIAZINtRatsCentral
factoriuss.c.,
p.o.4KI@:I:@@l—Methyl—2—butylhydrazine
@
intestine,
olfactoriuss.c.,
2 HCIRatsLarge
bulbus
.‘ic'
PHENYLHYI*AZINE
CCIMiceLungsp.o.2
mated that well over 100 synthetic substituted hydrazines
are used today in the environment (26).
NATURALLY OCCURRING HYDRAZINES
Hydrazine in Tobacco
Hydrazine
(Chart
1F) has been found in both tobacco and
tobacco smoke (23). At first the presence of hydrazine was
attributed
to maleic hydrazide,
a widely used plant growth
retardant, which is sprayed on tobacco plants. Actually, the
technical
graded maleic hydrazide
contains free hydrazine.
zinc derivatives of as yet undetermined
structures.
In
addition, the occurrence of 4-hydroxymethylbenzene
diazo
nium ion (19), phenol, “y-L-glutamyl-4-hydroxybenzene, and
possibly -y-L-glutamyl-3,4-benzoquinone
(48-5 1) in the
mushroom was reported. Also, a substance closely similar
in structure to agaritine N-('y-L-glutyamyl)-p-hydroxyani
line has been isolated (12) from the European “champig
non―Agaricus hortensis (apparently it is the same as A.
bisporus).
The estimated United States A . bisporus consumption
(production plus imports) totaled approximately
pounds from July 1972 to June 1973 (47).
The presence
More recently, however, hydrazine has been identified in was discovered
tobacco grown under well-defined conditions, to which
maleic hydrazide has not been added. The actual amount of
hydrazine in each cigarette was shown to be 30 ng (24). This
of hydrazines
in the cultivated
300 million
mushroom
in studies directed toward investigation of
metabolism of nonprotein amino acids. In 1962 and in
subsequent years when the tumor induction capabilities of
hydrazine and its derivatives became known, it was appar
means actually that hydrazine occurs naturally in the ently unnoticed by the investigators working with the
tobacco plants.
Hydrazines
in Mushrooms
Agaricus
bisporus.
Levenberg
(17, 18) reported in 1960
the isolation of agaritine from A . bisporus, the most
commonly eaten commercial mushroom in the United
States. This compound occurs predominantly in the fruiting
mushrooms.
Gyromitra esculenta. List and Luft's (21, 22) analytical
investigations showed that the extracts of one of the wild
and edible mushrooms,
Gyromitra
escu!enta, contained
gyromitrin,
an acetaldehyde
formylmethylhydrazone,
Nmethyl-N-formyl
hydrazine, and methylhydrazine.
Subse
quently, they postulated that the 2 latter chemicals were
produced from gyromitrin by hydrolysis during maceration
and cooking (Chart lC to E). When the mushrooms are
and its concentration
diminishes
with age. Subsequently, Daniels et a!. (3) and Kelly et a!. cooked in an open kettle, methylhydrazine is lost by steam
body of young mushrooms
(15) isolated
agaritine
from mushroom
sporophores
that
distillation and no toxicity is observed. When prepared in a
dish, the compounds
are not lost, and in this
condition mild hydrazine poisoning may be discerned (16).
yielded 0.04% based on fresh tissue weight and confirmed its closed
structure
as
phenylhydrazine
@-N-[―y-L(+
)-glutamyl]-4-hydroxymethyl
by degradation and synthesis (Chart
IA).
More recently in this laboratory, agaritine was also charac
terized and isolated in the mushroom. Preliminary toxicity
studies with agaritine were performed
in mice and published
recently (38, 45). Gigliotti and Levenberg (8, 9) also found
an enzyme in the mushroom, ‘y-glutamyltransferase,that
catalyzes the breakdown of agaritine to L-glutamate and
4-hydroxymethylphenylhydrazine
(Chart 1B). Agaritine
was found in comparable quantities in 10 other species
belonging to the genus Agaricus. Only 5 other species
belonging
to the sylvaticus
subgroup
were devoid of the
compound (20). Furthermore, 3 other members of the
Agaricaceae are believed to contain other aromatic hydra
DECEMBER
Furthermore, it was demonstrated recently that this mush
room contains up to 0.3% gyromitrin and 0.05% N-methyl
N-formylhydrazine
(30). Also, an extensive literature survey
was compiled dating from 1782, which documents the
various human mushroom poisoning cases attributed to G.
esculenta (7). In Germany alone in 1930, the estimated
imported quantity of this mushroom was 350,000 kg (7). It
also grows in the United States and Canada, mainly in
sandy soil under pine trees (29). Quantitative data on its
consumption by the human population in North America is
not available.
Only 2 hydrazines,
found or postulated
hydrazine
and monomethylhydrazine,
to exist in the tobacco and mushrooms
1975
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3695
B. Toth
CH2OH
‘4
NH-NH-C-CH@-CH2-CH--COO
AGARITINE, @8- N—(y-L (+1- GLUTAMYL)-4-
NYDRCXYMETHYLPHENYLHYDRAZINE
I
CH@OH
0
@
NH@+
II
a
I
+ H@C-CH2@CH2-CH-COO
@@NH2
L-ILUTAMIC
ACID
4- KYONOXYMETHYLPHENYLHYDNAZ*I(
CH3
C.
CHçCHN41@CHO
GY@0MIT@N,AOETALDENYOEMETHYLFO@MYLHYDNAZONE
@H3
0
H2N-N-CHO+CH@—CHO
N—METHYL—N--FOAVYL
HYDRAZINE
E
H2N—NH--CH3
+H—C02 H
METHYLHYDNAZINE
HEN- NH2
HYDRAZINE
Chart
proved
carcinogenic
compounds,
as
in animals
I . Chemical
structures
of naturally
( I , 35, 40). The other 4
identified and characterized
in mushrooms
@-N-[―y-L(+)-glutamyl]-4-hydroxymethylphenylhy
drazine,
4-hydroxymethylphenylhydrazine,
acetaldehyde
formylmethylhydrazone,
and N-methyl-N-formylhydra
zinc, have not been studied by others thus far for cancer
inducing capabilities.
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3697
Synthetic and Naturally Occurring Hydrazines as Possible
Cancer Causative Agents
Bela Toth
Cancer Res 1975;35:3693-3697.
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