[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

SUMMARY SYNTHETIC HYDRAZINES

The various synthetic substituted hydrazines, which cause tumors in animals, are briefly enumerated. To date, 19 of Studies on the carcinogenic potentialities of synthetic them have proved to be tumorigenic in animals. A number substituted hydrazines began in 1962, when it was shown of these chemicals are found today in the environment, in that the base compound hydrazine sulfate induced lung industry, in agriculture, and in medicine, and the human neoplasms in mice (1). Subsequently, a series of hydrazine population is exposed to a certain degree to some of them. derivatives were investigated in various laboratories for Hydrazine also occurs in nature in tobacco and tobacco tumor-inducing capabilities. These studies clearly demon smoke. The three other naturally occurring hydrazine strated that these chemicals are indeed powerful tumori compounds are N-methyl-N-formylhydrazine, which oc genic substances in mice, hamsters, and rats, due to their curs in the wild edible mushroom, Gyromitra esculenta, tumor-inducing abilities in the intestines, brain, lungs, and @-N-[―y-L(+)-glutamylJ-4-hydroxymethylphenyl blood vessels, liver, breasts, kidneys, etc. Now, we know of hydrazine and 4-hydroxymethylphenylhydrazine, whkh 19 hydrazine derivatives that have been shown to be tumor are found in the commonly eaten cultivated mushroom, inducers. These include, in addition to hydrazine (1, 32), Agaricus bisporus. Tumorigenesis studies with the natu methyl- (35, 40), 1,2-dimethyl- (6, 27, 36, 46, 52), 1,1- rally occurring hydrazines are in progress. dimethyl- (28, 37), benzoyl- (2, 34), phenyl- (2), 2-hydrox yethyl- (I I), 1,2-diethyl- (5), l-acetyl-2-isonicotinoyl- (39) hydrazines; N-isopropyl-a- (2-methythydrazino)-p-tolua INTRODUCTION mide (13, 14); and l-isonicotinoyl-2-isopropyl- (2), or thometoxybenzoyl- (2), paramethoxybenzoyl- (2), 1-meth Interest in chemical carcinogenesis in the past few yl-2-butyl- (4), l-methyl-2-benzyl- (4), ethyl- (42, 44), decades has focused on the possible roles of synthetic n-butyl- (44), 1-carbamyl-2-phenyl- (4 1), carbamyl- (43), chemicals that may cause cancer in man. This appeared and n-amyl- (33, 38) hydrazines. Their names, chemical justifiable on the. grounds of recent estimates that approxi structures, treatments, and action sites are summarized in mately 200,000 new chemicals enter our environment each Table 1. year. If only 1% of these chemicals enter at reasonably high These studies received particular attention because syn levels, this means that man may be exposed to around 2,000 thetic hydrazines are present in the environment and are new chemicals annually. To date, around 6,000 chemicals used in industry, agriculture, and medicine. They include have been studied for carcinogenic activities; of these, hydrazine, monomethylhydrazine, and 1,l-dimethylhydra approximately 1,000 compounds have thus far been found zinc, which are components of rocket fuels (26); carbamyl to be tumorigenic in animals. According to some experts, hydrazine, an industrial and laboratory reagent (26); 2- the exogenous hazardous agents are to a large extent hydroxyethylhydrazine, a ripener for pineapple and other responsible for the cancer incidence in the human popula plants (10); phenylhydrazine, used in treatment of polycy tion. themia vera (26); 1-isonicotinoyl-2-isopropylhydrazine, an The aim of this report is to draw attention to both the antidepressant and antituberculotic drug (3 1, 53); and synthetic and naturally occurring derivatives of hydrazine. N-isopropyl-a-(2-methylhydrazino)-p-toluamide, an an The synthetic hydrazines in recent years were shown to tineoplastic agent (25). To what extent humans are exposed produce tumors in animals, and therefore they may play a to the industrial hydrazines is presently not known. We do role in the etiology of human cancer. With the exception of not even have data concerning whether or not the pineapple hydrazine itself, the other naturally occurring derivatives of fruit contains the ripening agent. The amounts of these this compound, however, have thus far not been studied for various hydrazines used as therapeutic drugs are known and tumor-inducing abilities. they are not administered, however, on massive scales. The fact should be also emphasized that all hydrazine aRecipient of USPHS Research Career Development Award K04-42,552 from the National Cancer Institute. derivatives studied in laboratory animals were found (19 Received June 5, 1975; accepted August 26, 1975. altogether) to be tumor-producing substances. It is esti

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Table I Tumorigenic hydrazinecompounds

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, vesselsp.o.33P.O.2,34p.o.44P.O.43p.o.41s.c.5p.o.28,37Miceblood N-Amylhydrazine HCI

K@N@*2 Mice Lungs, lymphoreticular tissue kIIZOYUIYDIAZIII

NH,—NH—CH2—CH,—CH2—CH,. Mice Lungs N Butylhydrazine HC1

NH,—NH---CO—NH2. HCI M ice Lungs, blood vessels Carbamylhydrazine . HCI

Mice Lungs

CH,—CH,—NH—NH—CH2—CH1 Rats Lymphoreticular and nerve 1,2-Diethylhydrazine• tissues,liver,ethmotur binal

(CH1), N—NH, Mice Lungs. blood vessels, kidney, 1.1-Dimethyihydrazine liver

CH,—NH—NH—CH, Colon, lungs, blood vessels p.o. 52 1,2-Dimethyihydrazine . 2HC1 27,36Ratss.c.,Hamsterss.c., Liver, stomach, intestine, i.m.,p.o.46, bloodvessels p.o.6Micep.o.42MiceIntestine

NH,—NH—CH,—CH,. Lungs, blood vessels Ethylhydrazine . HCI

NH,—NH,. H,SO4 liver Hydrazine sulfate 32MiceLiverp.o.11MiceLungsp.o.2MiceRatsLungs, Liver, lungsp.o. p.o.1

NH,—NH—CH,—CH,OH 2-Hydroxyethythydrazine

1I$ONICOTIIOYI.2IIOPIOPYU4YDMZI@(

lymphoreticular i.p. QCr*-IC-012 @J co@NI1 tissue, kidney N-Isopio@vi-d-(2-ICTwyi.syDI*zIuo)- 14MiceLungsp.o.2MiceLungsp.o.2MiceRatsLungs, Breast, lungs, blood p.o., i.p.13 P-TO@uMIX CCI vesselsp.o.,

2043

O-@ThOXYIINZOYUIYDIAZINI

0I@0

P—@THOXYWIZOYLHYDIAZINt

CH,—NH—NH, Methylhydrazine HamstersLungsKupffer cells, cecump.o. p.o.35 40

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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:@@- intestine, bulbus l—Methyl—2—butylhydrazine 2 HCIRatsLarge olfactoriuss.c., @ .‘ic'

PHENYLHYI*AZINE CCIMiceLungsp.o.2

mated that well over 100 synthetic substituted hydrazines zinc derivatives of as yet undetermined structures. In are used today in the environment (26). 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 NATURALLY OCCURRING HYDRAZINES mushroom was reported. Also, a substance closely similar in structure to agaritine N-('y-L-glutyamyl)-p-hydroxyani Hydrazine in Tobacco line has been isolated (12) from the European “champig non―Agaricus hortensis (apparently it is the same as A. Hydrazine (Chart 1F) has been found in both tobacco and bisporus). tobacco smoke (23). At first the presence of hydrazine was The estimated United States A . bisporus consumption attributed to maleic hydrazide, a widely used plant growth (production plus imports) totaled approximately 300 million retardant, which is sprayed on tobacco plants. Actually, the pounds from July 1972 to June 1973 (47). technical graded maleic hydrazide contains free hydrazine. The presence of hydrazines in the cultivated mushroom More recently, however, hydrazine has been identified in was discovered in studies directed toward investigation of tobacco grown under well-defined conditions, to which metabolism of nonprotein amino acids. In 1962 and in maleic hydrazide has not been added. The actual amount of subsequent years when the tumor induction capabilities of hydrazine in each cigarette was shown to be 30 ng (24). This 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. mushrooms. Gyromitra esculenta. List and Luft's (21, 22) analytical Hydrazines in Mushrooms investigations showed that the extracts of one of the wild and edible mushrooms, Gyromitra escu!enta, contained Agaricus bisporus. Levenberg (17, 18) reported in 1960 gyromitrin, an acetaldehyde formylmethylhydrazone, N- the isolation of agaritine from A . bisporus, the most methyl-N-formyl hydrazine, and methylhydrazine. Subse commonly eaten commercial mushroom in the United quently, they postulated that the 2 latter chemicals were States. This compound occurs predominantly in the fruiting produced from gyromitrin by hydrolysis during maceration body of young mushrooms and its concentration diminishes and cooking (Chart lC to E). When the mushrooms are with age. Subsequently, Daniels et a!. (3) and Kelly et a!. cooked in an open kettle, methylhydrazine is lost by steam (15) isolated agaritine from mushroom sporophores that distillation and no toxicity is observed. When prepared in a yielded 0.04% based on fresh tissue weight and confirmed its closed dish, the compounds are not lost, and in this structure as @-N-[―y-L(+)-glutamyl]-4-hydroxymethyl condition mild hydrazine poisoning may be discerned (16). phenylhydrazine by degradation and synthesis (Chart IA). Furthermore, it was demonstrated recently that this mush More recently in this laboratory, agaritine was also charac room contains up to 0.3% gyromitrin and 0.05% N-methyl terized and isolated in the mushroom. Preliminary toxicity N-formylhydrazine (30). Also, an extensive literature survey studies with agaritine were performed in mice and published was compiled dating from 1782, which documents the recently (38, 45). Gigliotti and Levenberg (8, 9) also found various human mushroom poisoning cases attributed to G. an enzyme in the mushroom, ‘y-glutamyltransferase,that esculenta (7). In Germany alone in 1930, the estimated catalyzes the breakdown of agaritine to L-glutamate and imported quantity of this mushroom was 350,000 kg (7). It 4-hydroxymethylphenylhydrazine (Chart 1B). Agaritine also grows in the United States and Canada, mainly in was found in comparable quantities in 10 other species sandy soil under pine trees (29). Quantitative data on its belonging to the genus Agaricus. Only 5 other species consumption by the human population in North America is belonging to the sylvaticus subgroup were devoid of the not available. compound (20). Furthermore, 3 other members of the Only 2 hydrazines, hydrazine and monomethylhydrazine, Agaricaceae are believed to contain other aromatic hydra found or postulated to exist in the tobacco and mushrooms

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CH2OH

‘4

NH-NH-C-CH@-CH2-CH--COO AGARITINE, @8-N—(y-L (+1- GLUTAMYL)-4- NYDRCXYMETHYLPHENYLHYDRAZINE I CH@OH 0 NH@+ II I @ a + H@C-CH2@CH2-CH-COO @@NH2 L-ILUTAMICACID

4- KYONOXYMETHYLPHENYLHYDNAZ*I(

CH3 C. CHçCHN41@CHO GY@0MIT@N,AOETALDENYOEMETHYLFO@MYLHYDNAZONE

@H3 0 H2N-N-CHO+CH@—CHO N—METHYL—N--FOAVYLHYDRAZINE

E H2N—NH--CH3 +H—C02 H METHYLHYDNAZINE HEN- NH2 HYDRAZINE

Chart I. Chemical structures of naturally occurring hydrazines and a hydrazone.

proved carcinogenic in animals ( I, 35, 40). The other 4 Colon and Antecedent Epithelium, pp. 267-269. Springfield, III.: compounds, identified and characterized in mushrooms Charles C Thomas, Publisher, 1970. as @-N-[―y-L(+)-glutamyl]-4-hydroxymethylphenylhy 5. Druckrey, H., Preussman, R., Matzkies, F., and Ivankovic, S. drazine, 4-hydroxymethylphenylhydrazine, acetaldehyde Carcinogene Wirkung von l.2-Diilthylhydrazin an Ratten. Naturwis senschaften, 53: 557-558, 1966. formylmethylhydrazone, and N-methyl-N-formylhydra 6. Druckrey, H., Preussman, R., Matzkies, F., and Ivankovic, S. zinc, have not been studied by others thus far for cancer Selective Erzeugung von Darmkrebs bei Ratten durch 1,2-Dimethyl inducing capabilities. hydrazin. Naturwissenschaften, 54: 285-286, 1967. 7. Franke, S., Freimuth, U., and List, P. H. Uber die Giftigkeit der Friihjährslorchel Gyromitra (Helvella) esculenta Fr. Arch. Toxikol. REFERENCES 22:293-332,1967. 8. Gigliotti, H., and Levenberg, B. Enzymatic Transfer of the -y-Gluta I. Biancifiori, C., and Ribacchi, R. Pulmonary Tumours in Mice Induced myl Group between Naturally Occurring Aniline and Phenylhydrazine by Oral Isoniazid and Its Metabolites. Nature, 194: 488-489, 1962. Derivatives in the Genus Agaricus. Biochim. Biophys. Acta, 81: 2. Clayson, D. B., Biancifiori, C., Milia, U., and Giornelli-Santilli, F. E. 618-620.1964. The Induction of Pulmonary Tumours in Balb/Cb/Se Mice by 9. Gigliotti, H., and Levenberg, B. Studies on the y-Glutamyltransferase Derivatives of Hydrazine. In: L. Seven (ed), Lung Tumors in of Agaricus bisporus. J. Biol. Chem., 239: 2274-2284, 1964. Animals, Proceedings of the Quadrennial Conference on Cancer, 10. Gowing, D. P., and Leeper, R. W. Induction of Flowering in Pineapple University of Perugia Department of Cancer Research, Perugia, by Beta-hydroxyethylhydrazine. Science, 122: 1267, 1955. Italy,1966,pp.869-880. 11. Innes, J. R. M., Ulland, B. M., Valerio, M. G., Petrucelli, L., 3. Daniels, E. G., Kelly, R. B., and Hinman, J. W. Agaritine: An Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk, H. L., Improved Isolation Procedure and Confirmation of Structure by Gail, J. J., Klein, M., Mitchell, I., and Peters, J. Bioassay of Synthesis. J. Am. Chem. Soc., 83: 3333-3334, 1961. Pesticides and Industrial Chemicals for Tumorigenicity in Mice. J. 4. Druckrey, H. Production ofColonic Carcinomas by 1,2-Dialkylhydra Natl.Cancerlnst.,42:1101-1114,1969. zines and Azoxyalkanes, In: W. J. Burdette (ed), Carcinomas of the 12. Jadot, J., Casimir, J., and Renard, M. Separation et Caracterisation

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Bela Toth

Cancer Res 1975;35:3693-3697.

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