Cancer Induction in Mice by Feeding the Raw False Morel Mushroom Gyromitra Esculenta1

Home , False morel, Gyromitra, Gyromitra esculenta, Gyromitra gigas, Gyromitrin, Helvella

[CANCER RESEARCH 52, 2279-2284, April 15. 1992] Cancer Induction in Mice by Feeding the Raw False Morel Mushroom Gyromitra esculenta1

Bela Toth,2 Kashinath Patii, HeikkÃ®Pyysalo, Carol Stessman, and Peter Gannett

The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198 [B. T., K. P., C. S.J; Finnish Customs Laboratory, Espoo, Finland Â¡H.P.]; and West Virginia University, Morgantown, West Virginia 26506 [P. G.]

ABSTRACT diet in regular pellets (Allied Mills, Inc., Chicago, IL) until 6 weeks of age. Afterwards the mice were given a semisynthetic diet (8) prepared One of the false morel mushrooms, Gyromitra esculenta, was admin by us. Tap water was provided ad libitum from birth until natural death. istered p.o. to Swiss mice that were 6 weeks old at the beginning of the Dr. Heikki Pyysalo and his colleagues collected the GE4 mushroom experiment. The mushrooms were fed to the mice for 3 days and were (Fig. 1) in southern and eastern Finland. A mycologist (Dr. Mauri followed by a semisynthetic diet for 4 days each week for life. The Korhonen) taxonomically identified all the specimens as GE by using treatment induced tumors in the lungs, nasal cavity, blood vessels, fore- the guidelines of Harmaja and Weber (9,10). There is only one species stomach, glandular stomach, cecum, and liver in the following incidences: in this region. The mushrooms were stored in dry ice after harvest. 80, 10, 50, 16, 4, 28, and 6% in females, and 70, 12, 32, 18, 20, 22, and They then were deep-frozen at -25Â°C.Within 2 weeks, the mushrooms 12% in males. In the untreated controls, the corresponding tumor inci were shipped frozen with dry ice to Omaha by air. Upon arrival, the dences were 28, 0, 14, 0, 0, 8, and 0% in females and 38, 0, 6, 0, 0, 8, mushrooms were inspected, found to be completely frozen, and placed and 2% in males. The light microscopic examination revealed the typical in a deep freeze at -15Â°Cin the Eppley Institute. On each feeding day, appearance of adenomas and adenocarcinomas of lungs, adenomas and an appropriate amount was defrosted and given to the animals. adenocarcinomas of nasal cavities, hemangiomas and hemangiosarcomas Several samples, approximately 30 g, of the fresh mushroom were of blood vessels, squamous cell papillomas and carcinomas of the fore- thawed, placed in a Soxhlet thimble, and continuously extracted with stomach, adenomas and adenocarcinomas of the glandular stomach, diclini ether for 24 h. The ether extract was then dried over sodium polypoid adenomas and adenocarcinomas of the cecum, and hepatomas. sulfate, concentrated to 5 ml by distillation, and analyzed for gyromitrin The work demonstrates the carcinogenic action of the raw G. esculenta and A'-methyl-A'-formylhydrazine by gas chromatography (DB-1, mushroom. 70Â°C).The concentration of gyromitrin and A'-methyl-A'-formylhydra zine were 44 and 4 mg/kg, respectively. Toxicity studies were carried out with GE prior to the chronic INTRODUCTION experiment. GE was fed ad libitum for 4.5, 4, 3.5, 3, and 2.5 days each week, followed by semisynthetic diet for the rest of the week for a total Gyromitra esculenta (Fig. 1) is a wild edible mushroom be of 70 days. Each group consisted of 8 animals (4 female, 4 male). longing to the false morel mushroom family. On the North Taking into account four parameters (survival rates, body weights, dose of mushroom, and histolÃ³gica! changes), feeding GE for 3 days was American continent, 11 such mushroom species exist, while in Europe only 2-3 are known (1). It is estimated that over found to be suitable for the chronic experiment. This toxicity technique was developed in this laboratory (11). 100,000 people annually consume this fungus in the United The chronic experimental groups and the controls were the following: States.3 G. esculenta is also eaten in substantial quantities in Group 1. GE was fed ad libitum for 3 days, followed by semisynthetic other continents, particularly in Northern and Eastern Europe diet for 4 days of each week for the life span of 50 female and 50 male (2, 3). The consumption is more prevalent in rural areas, mice that were 6 weeks (48 days) old at the beginning of the experiment. although the mushroom is also marketed in canned and dried Group 2. Consisted of 50 female and 50 male mice, 6 weeks (44 days) forms in certain parts of the world (2, 3). old at the beginning of the experiment. They served as untreated Systematic carcinogenesis investigations have been con controls. ducted in animals with six hydrazine ingredients of this mush The experimental and control animals were carefully checked and weighed weekly, and the gross pathological changes were recorded. The room in this laboratory. These studies clearly demonstrated the animals either were allowed to die or were killed with ether when found highly carcinogenic nature of these compounds which induced in poor condition. Complete necropsies were performed on all animals. cancers in nearly a dozen organs and tissues of mice and All organs were examined macroscopically and were fixed in 10% hamsters (4-7). buffered formalin. The liver, spleen, kidneys, bladder, thyroid, heart, The present work was undertaken to ascertain the possible pancreas, testes, ovaries, preputial and clitoral glands, brain, nasal carcinogenicity of the raw G. esculenta by p.o. lifelong inter turbinais, forestomach, glandular stomach, duodenum, jejunum, ileum, mittent administration in mice. cecum, colon, rectum, at least four lobes of the lungs of each mouse, and organs showing gross pathological changes were studied histologically. Sections from these tissues were stained routinely with hematox- ylin and eosin and examined by light microscopy. MATERIALS AND METHODS Statistical Analysis. The statistical analysis was performed by using the Fisher's exact test for 2 x 2 tables (12). Swiss albino mice from a colony randomly bred by us since 1951 were used. They were housed in plastic cages on granular cellulose bedding, separated by sex into groups of 5, and given Wayne Lab-Blox RESULTS Received 8/23/91; accepted 2/12/92. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in The survival rates of GE-treated and control mice are re accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by USPHS Grant CA 44075. corded in Table 1. The data show that the mushroom treatment 1To whom requests for reprints should be addressed, at The Eppley Institute had no substantial effect on survival when compared with the for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198. 4The abbreviations used are: GE, Gyromitra esculenta; MFHO, 3O. K. Miller, personal communication, 1976. methylformylhydrazone. 2279

benign adenomas usually were circumscribed and the glandular formations were lined by the cuboidal and columnar cells (Fig. 2). In other instances, the olfactory epithelium developed into the characteristic patterns of adenocarcinoma, which were usu ally larger than the benign tumor; they showed moderate inva- siveness, although no metastasis was observed. Otherwise, grossly and histopathologically, these tumors were similar to those described by other investigators (15). Tumors of Blood Vessels. Of the treated females, 25 (50%; P < 0.0002) developed vascular tissue tumors. Of these, 12 mice had hemangiomas in livers, 10 mice had hemangiosarcomas in livers, 1 mouse had a hemangioma in spleen, 1 mouse had a hemangioma in ovary, and 1 mouse developed a hemangiosarcoma in lungs. Of the treated males, 16 (38%; P < 0.001) developed blood vessel neoplasms. Of these, 9 mice had heman Fig. 1. Gyromitra esculenta is one of the wild mushrooms belonging to the giomas in livers and 7 mice developed hemangiosarcomas in false morel family. Gross specimen. livers. In the untreated control females, 7 (14%) developed vascular tissue tumors. Of these, 3 had hemangiomas in livers, 1 had a untreated controls. In addition, the average weekly body weight hemangiosarcoma in liver, 2 had hemangiomas in ovaries and curves of the treated and untreated mice have not shown any 1 mouse developed hemangiomas in the uterus and s.c. tissue. significant difference until 100 week of age. Afterwards, the In the untreated control males, 3 (6%) developed blood vessel body weights of the untreated mice were significantly higher tumors. Of these, 2 had hemangiomas in livers and 1 mouse than of the corresponding treated groups. developed a hemangiosarcoma in liver. The number, percentages of mice with tumors, and their ages In other respects, grossly and histopathologically, these tu at death (latent periods) are summarized in Table 2. The treat mors were similar to those found in earlier experiments in this ment induced tumors in the lungs, nasal cavity, blood vessels, laboratory (16, 17). forestomach, glandular stomach, cecum, and liver, which are Tumors of the Forestomach. Of the treated females, 8 (16%; described in detail below. P < 0.005) developed 8 squamous cell papillomas of this organ. Lung Tumors. Of the treated females, 40 (80%; P< 0.00001) Of the treated males, 9 (18%; P < 0.003) developed 16 neo developed 117 neoplasms in this organ. Of these, 24 mice had plasms in this organ. Of these, 8 mice had 15 squamous cell 62 adenomas, 2 mice had 2 adenocarcinomas, and 14 mice papillomas and the remaining mouse developed a squamous developed 31 adenomas and 22 adenocarcinomas. In the treated cell carcinoma. No forestomach tumor was found in the un males, 35 (70%; P < 0.0001) developed 81 lung tumors. Of treated controls. these, 22 mice had 42 adenomas, 2 mice had 2 adenocar Otherwise grossly and histologically, these tumors were sim cinomas, and 11 mice developed 24 adenomas and 13 ilar to those reported earlier in this laboratory (18). adenocarcinomas. Tumors of the Glandular Stomach. Of the treated females, 2 In the untreated control females, 14 (28%) developed 15 (4%) developed 2 adenocarcinomas in this organ. Of the treated neoplasms in this organ. Of these, 9 mice had 10 adenomas males, 10 (20%; P < 0.002) developed 11 tumors in this organ. and 5 mice developed 5 adenocarcinomas. In the untreated Of these, 1 mouse had 2 adenomas and 9 mice developed 9 control males, 19 (38%) developed 31 lung tumors. Of these, adenocarcinomas in the glandular stomach. 11 mice had 17 adenomas, 4 mice had 4 adenocarcinomas, and Most of the glandular stomach tumors grew into the lumen 4 mice developed 5 adenomas and 5 adenocarcinomas. of the organ, although sometimes they invaded the wall of the Macroscopically and histologically all lung tumors were sim stomach. These lesions often exhibited irregular sizes and ilar to those described earlier (13, 14). shapes of the gastric glands lined by cuboidal or columnar cells Tumors of the Nasal Cavity. Of the treated females, 5 (10%; (Fig. 3). In some cases, the tumor was well circumscribed and P< 0.04) developed 5 neoplasms in this tissue. Of these, 4 were was diagnosed as an adenoma. In other instances, particularly classified as adenomas and the remaining 1 as an adenocarci- when the neoplastic glands invaded the muscularis layer, the noma. In the treated males, 6 (12%; P < 0.02) developed 6 lesion was classified as an adenocarcinoma. No glandular stom nasal cavity tumors. Of these, 5 were classified as adenomas ach tumors were found in the control animals. and 1 as an adenocarcinoma. No nasal cavity tumors were In other respects macroscopically and histopathologically, found in the untreated controls. these tumors were similar to those described earlier in this The epithelial layer of the nasal cavities gradually increased laboratory (19). in thickness, presenting the appearance of hyperplasia. The Tumors of the Cecum. Of the treated females, 14 (28%;

Table 1 Treatment and survival rates in GE-lreated and control Swiss mice no.of wk)70464542458037403632902327252210010171611110411103120154113021140survivors (age in

GroupTreatment1 miceSOF50MSOFSOM10505050502050495050305049505040504848505050474749No.6048464547of GEeachweek p.o. for 3 days life2 for

Untreated controlsInitial

2280

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1992 American Association for Cancer Research. FALSE MOREL AND CANCER histiocytomas in hamsters. /V-Methyl-./V-formylhydrazine ad ministered under identical conditions as methylhydrazine caused tumors of the liver, lungs, blood vessels, bile ducts, and gallbladder in mice, and tumors of the liver, gallbladder, bile ducts, and malignant histiocytomas in hamsters. Acetaldehyde methylformylhydrazone induced tumors of the lungs, forestomach, and preputial and clitoral glands in mice. Pentanal meth ylformylhydrazone and hexanal methylformylhydrazone each elicited the development of tumors of the lungs, liver, and preputial glands in Swiss mice (4, 6). Finally, 3-methylbutanal methylformylhydrazone induced tumors in the lungs, liver, gallbladder, preputial glands, and thyroid in mice (5). The present administration of GE mushroom induced seven types of neoplasms in mice. Those of the lungs, blood vessels, forestomach, and liver were identical to those found in mice treated with the six chemical ingredients of this mushroom. In addition, Fig. 2. Adenoma of the nasal cavity. The lesion consists of columnar cells arranged in a single layer around irregular glandular spaces. H & E, x 80. tumors were induced in the nasal cavity, glandular stomach, and cecum of GE-fed mice. This discrepancy could be due to the additional, thus far unstudied, carcinogenic chemicals that may be present in GE. P< 0.001) developed 23 tumors in this organ. Of these, 13 had Medical literature has reported poisoning cases from G. 22 polypoid adenomas and 1 mouse developed an adenocarci- esculenta. Fatalities following the consumption of this fungus noma. Of the treated males, 11 (22%; P < 0.05) developed 22 have been reported in various countries (2). Recently, a review tumors in this organ. Of these, 10 mice had 18 polypoid adenomas and 1 mouse developed 3 polypoid adenomas and 1 adenocarcinoma. In the untreated control females, 4 (8%) developed 5 polypoid adenomas in this organ. In the untreated control males, 4 (8%) developed 5 polypoid adenomas in the cecum. These growths obtruded into the lumen of the cecum, show ing polypoid or cauliflower-like appearances, often obstructing ;\f-jf partially or completely the intestine. Histologically, the poly " * &W& ^ â€¢¿ poid adenomas consisted of irregular and deformed tubules and .#&â€¢â€¢ acini lined by the neoplastic epithelium. These structures spread vV â€¢¿-<-',. li' ... I f â€¢¿>â€¢...'?â€¢ . upward around the central fibrous stalk (Fig. 4). In adenocar- ' 'â€¢ ' ' '' ' ' ' cinomas, evidence of infiltrative activity was obvious. The pen etration of muscularis mucosae and invasions of submucosa were often present. Otherwise grossly and histologically, these tumors were sim ilar to those published previously in this laboratory (18). Liver Tumors. Of the treated females, 3 (6%) developed benign hepatomas. Of the treated males, 6 (12%; P < 0.06) Fig. 3. Adenocarcinoma of the glandular stomach. The atypical glandular formations are evident. The neoplastic glands are lined by cuboidal or columnar developed benign hepatomas. cells. H & E, x 80. In the untreated control males, one mouse developed a benign hepatoma while no such tumor was observed in the correspond ing females. In other respects macroscopically and histologically, the liver tumors were similar to those described previously in this labo * fi <*_Â£r-L ratory (16). ^: ^Ã„^SRfc >Â»>. "^-3 Other Tumors. In a number of instances, other types of neoplasms were observed in the treated animals shown in Table <â€¢â€¢¿

DISCUSSION This experiment shows that the lifelong administration from 6 weeks of age of GE for 3 days, followed by a semisynthetic diet for 4 days each week, induced tumors in seven organs and tissues of Swiss mice. Methylhydrazine, an ingredient of this mushroom, when Fig. 4. Polypoid adenoma of the cecum. Observe the central stalk composed given p.o. in the drinking water to mice, induced lung neo of connective tissue lined by the proliferative mucus-producing glandular struc plasms, and also induced tumors of the cecum and malignant tures. H & E, x 30. 2281

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1992 American Association for Cancer Research. FALSE MOREL AND CANCER Table 2 Treatment and tumor incidences in GE-trealed and control Swiss mice withForestomachAge Lungs Nasal cavity vesselsAge EffectiveGroup1TreatmentG and Age at at at at %50sex No. % death" No. death"No.103(85-122) No.50% death" %death"16

E p.o. for F 40 80 94(66-122) 5 10Age 25Blood 86(66-107) 8Animals 86(69-108) 3 days each week for lifeno.

50 M 35 70 97(56-140) 12 8(74-123) 16 32 91(74-111) 18 91(56-112)

Untreated 50 F 14 28 90(58-115) 14 97(60-129) controls

SOM 19 38 88(53-120)

Â°Averageand range in weeks. * Numbers in parentheses, age at death in weeks. describing the toxic syndrome attributed to G. esculenta poison lubrica, Spathularia flavida, and Neobulgaria pura, are members ings and the possible mode of action of the toxins was published of other mushroom families (24, 25). In an earlier study, feeding (3). of the cultivated mushroom in the Western hemisphere, Agar- Several investigators worldwide analyzed the G. esculenta icus bisporus, induced tumors in four organs and tissues of mushroom for hydrazines. The following types and amounts Swiss mice (26). Subsequently, in another laboratory, a diet were identified in it: acetaldehyde MFHO, 49.9 mg/kg; pro- containing a 30% dry powder of A. bisporus was given for 500 panal MFHO, 1.0 mg/kg; butanal MFHO, 0.6 mg/kg; 3-meth- days to 20 female rats. The treatment had no tumorigenic effect ylbutanal MFHO, 2.2 mg/kg; pentanal MFHO, 0.8 mg/kg; hexanal MFHO, 1.4 mg/kg; octanal MFHO, 0.2 mg/kg; trans- in the animals (27). This study can be criticized because the dry 2-octenal MFHO, 0.6 mg/kg; m-2-octenal MFHO, 0.3 mg/kg; mushroom probably contained less carcinogens (no measure /V-methyl-yV-formylhydrazine, 500 mg/kg (by dry weight); and ment was taken) than the fresh; it was given for a shorter time methylhydrazine, 14 mg/kg5 (20-23). It has been also shown (500 days versus life span); only one sex of animals was treated; that boiling decreases the levels of hydrazines in the mushroom too few rats were used; and, above all, humans rarely consume (23). dry A. bisporus. It is also known that several other relatives of In addition to the G. esculenta, other mushroom species also this fungus, all belonging to the Agaricaceae family, contain contain carcinogenic hydrazines. Some of the species, including carcinogenic hydrazines (28). To date, 22 mushroom species Gyromitra gigas, Helvetia crispa, and H. lacunosa, which also are known to contain 11 carcinogenic hydrazine analogues and belong to the Helvellaceae family, as does the G. esculenta (24, diazonium ions (7). 25). Other mushrooms, such as the Cyathipodia macropus, The G. esculenta mushroom fed in the present experiment Leptopodia elastica, Otidea onotica, Cudonia circinans, Leotia was obtained from Finland and was analyzed periodically for 5 L. Wallcave, personal communication. 1978. hydrazines. The concentrations of hydrazines were similar to 2282

tumors of: Glandular stomach Cecum Liver Age at Age at Age at death" No. death" No. death" No. Other organs 99(96-102) 14 28 90(76-102) 6 77(72-81 ) 6 malignant lymphomas (69,76,88,91,94,116) 3 osteomas (89, 107, 108) 2 adrenal cortical adenomas (116, 118) adenoma of gallbladder (72) adenocarcinoma of gallbaldder (87) granulosa cell tumor (118) adenoma of ovary (108) leiomyoma of uterus (72) leiomyosarcoma of uterus (76) adenoma of pituitary (118) adenocarcinoma of duodenum (103)

10 20 90(40-134) 22 99(76-123) 12 99(81 -123) 3 adenomas of gallbladder (85,88,88) 2 malignant lymphomas (88, 134) 2 adenocarcinomas of duodenum (76,90) 1 carcinoma of skin (96) 1 osteoma (97) 1 osteosarcoma (81) 1 fibrosarcoma, s.c. (74) 1 adenoma of anal gland (89) 1 malignant pericytoma (85) 1 adenocarcinoma of salivary glands (88) 1 adenoma of kidney (125) 1 adenocarcinoma of pancreas (14)

8 94(72-108) 9 malignant lymphomas (52,73,74.88,97,99,107,118,127) 5 adenocarcinomas of breasts (88,91,98,98,129) 4 adenomas of thyroids (82,98,98,129) 2 adenocarcinomas of thyroids (72,129) 2 osteomas (118,127) papilloma of skin (114) adenoma of bladder (88) hemangiopericytoma (63) leiomyoma of uterus (79) leiomyosarcoma of uterus ( 128) granulosa cell tumor (132)

87(75-119) 1 2 103 3 adenomas of thyroids (57,80,85) 2 malignant lymphomas (95,105) adenoma of anal gland (103) adenocarcinoma of anal gland (79) adrenal cortical adenoma (102) adenoma of seminal vesicles (84) adenocarcinoma of thyroid (95) leiomyosarcoma of arteries (79) fibrosarcoma, s.c. (103)

Toth, B., Taylor, J., and Gannett, P. Tumor induction with hexanal meth the values found in the North American G. esculenta, which ylformylhydrazone of Gyromitra esculenta. Mycopathologia, 7/5:65-71, were reported previously. 1991. Interestingly, the body weight of the animals fed the GE Toth, B. Carcinogenic fungal hydrazines. In Vivo, 5: 95-100, 1991. National Research Council: Subcommittee on Laboratory Animal Nutrition, mushroom for nearly 2 years increased steadily. This means Nutrient Requirements of Laboratory Animals, pp. 43-53. Washington, DC: that the treated mice obtained a nourishing diet during the main National Academy of Sciences, 1978. course of the experiment just like the untreated control animals. Harmaja, H. Notes on Gyromitra esculenta coll. and G. recurva a noteworthy species of Western North America. Karstenia, 19: 46-49, 1979. The uncooked G. esculenta mushroom was found to be car Weber, N. S. A morel hunter's companion. A guide to the true and false cinogenic in the present experiment. Earlier studies also have morels of Michigan. Lansing, MI: Two Peninsula Press, 1988. Toth, B. A toxicity method with calcium cyclamate for chronic Carcinogenesis shown that six hydrazine ingredients of this fungus acted sim experiments. Tumori, 58: 137-142, 1972. ilarly in rodents. Because this mushroom also is eaten un Armitage, P. Statistical inference. In: Statistical methods in medical research, cooked, humans should abstain from the consumption of the pp. 135-138. Oxford: Blackwell Scientific Publications, 1971. Toth, B., and Shimizu, H. l-Carbamyl-2-phenylhydrazine tumorigenesis in raw form of this species. Swiss mice. Morphology of lung adenomas. J. Nati. Cancer Inst., 52: 241- 251, 1974. Toth, B. Formylhydrazine Carcinogenesis in mice. Br. J. Cancer, 37: 960- 964, 1978. REFERENCES Stenback, F. Glandular tumors of the nasal cavity induced by diethylnitros- amine in Syrian golden hamsters. J. Nati. Cancer Inst., 50: 895-901, 1973. 1. Miller, O. K. Mushrooms of North America. New York: E. P. Dutton Co., Toth, B., Magee, P. N., and Shubik, P. Carcinogenesis study with dimethyl- Inc., 1972. nitrosamine administered orally to adult and subcutaneously to newborn 2. Simons, D. M. The mushroom toxins. Del. Med. J., 43: 177-187, 1971. Balb/c mice. Cancer Res., 24: 1712-1721, 1964. 3. Michelot, D., and Toth. B. Poisoning by Gyromitra esculenta â€”¿areview. J. Toth, B., and Wilson, R. B. Blood vessel tumorigenesis by 1,2-dimethylhy- Appi. Toxicol., //:235-243, 1991. drazine dihydrochloride (symmetrical). Gross, light and electron microscopic 4. Toth, B., and Raha, C. R. Carcinogenesis by pentanal methylformylhydra- descriptions. I. Am. J. Pathol., 64: 585-600, 1971. zone of Gyromitra esculenta in mice. Mycopathologia, 98: 83-89, 1987. Toth, B., Tomatis, L., and Shubik, P. Multipotential Carcinogenesis with 5. Toth, B., and Gannett, P. Carcinogenesis study in mice by 3-methylbutanal urethan in the Syrian golden hamster. Cancer Res., 21: 1537-1541, 1961. methylformylhydrazone of Gyromitra esculenta. In Vivo, Â¿'283-288. 1990. 19. Toth, B., Nagel, D., and Ross, A. Gastric tumorigenesis by a single dose of 2283

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Bela Toth, Kashinath Patil, Heikki Pyysalo, et al.

Cancer Res 1992;52:2279-2284.

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