Summary
Hamster embryos in utero on the 11th or 12th day of gestation were treated simultaneously with aminopyrine (Ap) and sodium nitrite (NaNO2) by oral administration of the compounds to the mothers by stomach tube. For measurement of induction of 8 AG-resistant mutations, the embryonic cells from treated and control mothers were cultured in MEM plus 10% FBS for 72 h and then selected in medium containing 10 or 20 μg/ml of 8 AG. The number of 8 AG-resistant colonies was markedly increased after co-administration of Ap and NaNO2, and slight induction of mutations was also observed in cells from mothers given NaNO2 alone. This treatment also caused morphological or malignant transformation of cultured cells. About 5-to 6-fold increase in the number of transformed colonies was observed in cells from mothers given Ap plus NaNO2. Cells from the transformed colonies produced tumors when implanted into the cheek pouches of young golden hamsters. These tumors were diagnosed as pleomorphic fibrosarcomas. Similar results were obtained with cells from embryos treated transplacentally with NDMA as positive controls. A single transplacental oral application of Ap at 200 mg/kg or of NaNO2 had only slight biological actions to the cultured embryonic cells. NDMA was produced in the stomach of animals treated simultaneously with Ap and NaNO2. A small amount of NDMA was also detected in the stomach after a single dose of NaNO2.
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Abbreviations
- 8 AG:
-
8-azaguanine
- NaNO2 :
-
sodium nitrite
- Ap:
-
aminopyrine
- NDMA:
-
N-nitrosodimethylamine
- MEM:
-
Eagle's minimal essential medium
- FBS:
-
fetal bovine serum
- DMEM:
-
Dulbecco's modified Eagle's medium
- DCM:
-
dichloromethane
References
Bartsch H, Malaveille C, Montesano R (1975) In vitro metabolism and microsome-mediated mutagenicity of dialkylnitrosamines in rat, hamster, and mouse tissue. Cancer Res 35:644–651
Braun R, Shöneich J, Ziebarth D (1977) In vivo formation of N-nitroso compounds and detection of their mutagenic activity in the host-mediated assay. Cancer Res 47:4572–4579
Couch DB, Friedman MA (1975) Interactive mutagenicity of sodium nitrite, dimethylamine, methyl urea, and ethylurea. Mutation Res 31:109–114
Gomez RF, Johnston M, Scinskey AJ (1974) Activation of nitrosomorpholine and nitrosopyrrolidine to bacterial mutagens. Mutation Res 24:5–7
Greenblatt M, Mirvish S (1971) Nitrosamine studies: Induction of lung adenomas by concurrent administration of sodium nitrite and secondary amine in Swiss mice. J Natl Cancer Inst 46:1092–1034
Heisier EG, Siclliano J, Krulick S, Feinberg J, Schwartz JH (1974) Changes in nitrate and nitrite content, and search for nitrosamines in storage-abused spinach and beets. J Arg Food Chem 22:1092–1032
Inui N, Nishi Y, Taketomi M, Yamada M (1978) A short-term, simple method for detection of N-nitrosocompounds produced from sodium nitrite and morpholine in stomach. Biochem Biophys Res Commun 81:310–314
Inui N, Nishi Y, Taketomi M, Mori M (1979) Transplacental action of sodium nitrite on embryonic cells of Syrian golden hamster. Mutation Res 66:149–158
Kazic T (1977) Agranulocytosis caused by pyrazolone derivatives (aminopyrine, aminophenazone, metamizol and etc.) Pharmacology 15:21–24
Laishes BA, Stich HF (1973) Repair synthesis and sedimentation analysis of DNA of human cells exposed to dimethylnitrosamine and activated dimethylnitrosamine. Biochem Biophys Res Commun 52:827–833
Lijinsky W, Conard F, Van de Bogart R (1972) Carcinogenic nitrosamines formed by drug/nitrite interactions. Nature 239:165–167
Lijinsky W, Taylor HW, Snyder C, Nettesheim P (1973) Malignant tumors of liver and lung in rats fed aminopyrine or heptamethyleneimine together with nitrite. Nature 244:176–178
Malling HV (1971) Dimethylnitrosamine: Formation of mutagenic compounds by interaction with mouse liver microsomes. Mutation Res 13:425–429
Matsukura N, Kawachi T, Sasajima K, Sano T, Sugimura T, Ito N (1977) Induction of liver tumors in rats by sodium nitrite and methylguanidine. Z Krebsforsch 90:87–94
Mirvish SS (1975) Formation of N-nitroso compounds: Chemistry, kinetics and in vivo occurrence. Toxicol Appl Pharmacol 31:325–351
Montesano R, Barstch H (1976) Mutagenic and carcinogenic N-nitroso compounds: Possible environmental hazards. Mutation Res 32:179–228
Reznikoff CA, Brankow DW, Heidelberger C (1973a) Establishment and characterization of a clone line of C3H mouse embryo cells sensitive to post-confluence inhibition of division. Cancer Res 33:3231–3238
Reznikoff CA, Bertram JS, Brankow DW, Heidelberger C (1973b) Quantitative and qualitative studies of chemical transformation of cloned C3H mouse embryo cells sensitive to post confluence inhibition of cell division. Cancer Res 33:3239–3249
Sander J, Bürkle G (1969) Induktion maligner Tumoren bei Ratten durch gleichzeitige Verfütterung von Nitrit und sekundären Aminen. Z Krebsforsch 73:54–66
Tannenbaum SR, Sinskey AJ, Weisman M, Bishop W (1974) Nitrite in human saliva. Its possible relationships to nitrosamine formation. J Natl Cancer Inst 53:79–84
Tsuda H, Inui N, Takayama S (1976) In vitro transformation of newborn hamster cells induced by sodium nitrite. Gann 67:167–173
Vogel E (1975) The relation between mutational pattern and concentration of chemical mutagens in Drosophila sperm. Mutation Res 29:383–396
Vogel E, Sobels FH (1976) Mutagenitätsprüfung an Drosophila als Instrument zur Erfassung potentieller Carcinogene. Zentralbl Biol 95:405–413
White JW (1975) Relative significance of dietary sources of nitrate and nitrite. J Arg Food Chem 23:886–891
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This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, and Culture, Japan, and a Grant from the Ministry of Health and Welfare, Japan
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Inui, N., Nishi, Y., Hasegawa, M.M. et al. Induction of 8-azaguanine-resistant mutation and neoplastic transformation of hamster embryonic cells by coadministration of sodium nitrite and aminopyrine. J Cancer Res Clin Oncol 97, 119–128 (1980). https://doi.org/10.1007/BF00409897
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DOI: https://doi.org/10.1007/BF00409897