Comparison of the Acute Toxicity of N-nitrosocimetidine with Three Structurally Related Carcinogens in the Rat

Abstract

The acute toxicity of N-nitrosocimetidine, the nitrosated derivative of the histamine H₂-receptor blocking agent cimetidine, was compared with the toxicities of three structurally related nitroso compounds known to be potent carcinogens, namely N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, and N-methyl-N-nitrosourethane, and also with the parent drug cimetidine. The acute toxicity of each compound was investigated in 6-week-old female Fischer-344 rats by estimating the median lethal doses via three different routes of administration, and by assessing the sequence of histopathological alterations induced. According to median lethalities, all three known carcinogens were substantially more toxic than nitrosocimetidine whether administered by the intravenous, intraperitoneal, or oral routes. The widest margin of difference was represented by orally administered N-methyl-N-nitrosourea, the median lethal dose being 59 times greater than oral N-nitrosocimetidine. By this method, the acute toxicities of N-nitrosocimetidine and the parent drug cimetidine were virtually identical for each of the three routes of administration. Sequential histological assessment indicated that the three known carcinogens induced specific pathological alterations mainly in organs which were also known to be targets for their carcinogenic activity. In contrast, no tissue lesions of a specific nature were associated with N-nitrosocimetidinc or cimetidine in this study. The comparable results with N-nitrosocimetidine and the parent drug provide biological support for previously obtained biochemical data which suggested that N-nitrosocimetidine is rapidly denitrosated to cimetidine in the rat.

References

1. Abou-Gharbia MA , Pylypiw H , Harrington GW , and Swern D (1981). Synthesis of N-nitrosocimetidine hydrate and nitrate and tritium-labeling studies. J. Organic Chem. 46:2193–2194.

2. Athanasiou K and Kyrtopoulos SA (1981). Induction of sister chromatid exchanges and chromosome aberrations in cultured mammalian cells by nitro-socimetidine. Cancer Lett. 14:71–75.

3. Bavin PMG , Durant GJ , Miles PD , Mitchell RC , and Pepper ES (1980). Nitrosation of cimetidine (N“-cyano-N-methyl-N1- 2[(5-methylimidazol-4-yl) methylthio]ethyl guanidine). J. Chem. Res. (Synopses, 6): 21–213.

4. Barrows LR , Gombar CT , and Magee PN (1982). Mutation, DNA labeling and transformation of BHK-21/CL 13 cells by MNNG, and nitrosocimetidine. Mutation Res. 102:145–158.

5. Brimblecombe RW , Duncan WAM , Durant GJ , Emmett JC , Ganellin CR , Leslie GB , and Parsons ME (1978). Characterization and development of cimetidine as a histamine H2-receptor antagonist. Gastroenterology 74:339–347.

6. De Flora S and Picciotto A (1980). Mutagenicity of cimetidine in nitrite-enriched human gastric juice. Carcinogenesis 1:925–930.

7. Druckrey H , Preussmann R , Ivankovic S , and Schmähl D (1967). Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch 69:103–201.

8. Elder JB , Ganguli PC , and Gillespie IE (1979). Cimetidine and gastric cancer. Lancet i: 1005–1006.

9. Fujimura S , Kogure K , Sugimura T , and Takayama S (1970). The effect of limited administration of N-methyl-N'-nitro-N-nitrosoguanidine on the induction of stomach cancer in rats. Cancer Res. 30:842–848.

10.

10. Gombar CT and Magee PN (1982). DNA-methylation by nitrosocimetidine and N-methyl-N'-nitro-N-nitrosoguanidine in the intact rat. Chem.-Biol. Interact. 40:149–157.

11.

11. Habs M , Deutsch-Wenzel R , Preussmann R , and Schmähl D (1978). Induction of gastric tumors in BD-VI rats by single application of N-methyl-N'-nitro-N-nitrosoguanidine in dimethylsulfoxide (DMSO). Z. Krebsforsch. 91:183–188.

12.

12. Habs M , Schmähl D , Eisenbrand G , and Preussmann R (1982). Carcinogenesis studies with N-nitrosocimetidine, Part II: Oral administration to Sprague-Dawley rats. In: Banbury Report: Nitrosamines and Human Cancer, PN Magee (ed). Cold Spring Harbor Laboratory 12: 403–405.

13.

13. Hawker PC , Muscroft TJ , and Keighley MRB (1980). Gastric cancer after cimetidine in patient with two negative pre-treatment biopsies. Lancet i: 709–710.

14.

14. Henderson EE , Basilio M , and Davis RM (1981). Cellular DNA damage by nitrosocimetidine: A comparison with N-methyl-N'-nitro-N-nitrosoguanidine and X-irradiation. Chem.-Biol. Interact. 38:87–98.

15.

15. Ichinotsubo D , Mackinnon EA , Liu C , Rice S , and Mower HF (1981). Mutagenicity of nitrosated cimetidines. Carcinogenesis 2:261–264.

16.

16. Ipsen J and Feigl D (1970). Bioassay. In: Bancroft's Introduction to Biostatistics, 2nd ed. Harper and Row, Publishers, New York, pp. 163–170.

17.

17. Jensen DE (1978). Reaction of DNA with alkylating agents. Differential alkylation of poly (dA-dT) by methylnitrosourea and ethylnitrosourea. Biochemistry 17:5108–5113.

18.

18. Jensen DE (1983). Denitrosation as a determinant of nitrosocimetidine in vivo activity. Cancer Res. 43:5258–5267.

19.

19. Jensen DE and Gombar CT (1982). Factors which influence the in vivo methylation potential of nitrosocimetidine. In: Banbury Report: Nitrosamines and Human Cancer, PN Magee (ed). Cold Spring Harbor Laboratory 12: 379–395.

20.

20. Jensen DE and Magee PN (1981). Methylation of DNA by nitrosocimetidine in vitro. Cancer Res. 41:230–236.

21.

21. Koestner AW , Ruecker FA , and Koestner A (1981). Morphology and pathogenesis of tumors of the thymus and stomach in Sprague-Dawley rats following intragastric administration of methyl nitrosourea (MNU). Intl. J. Cancer 20:418–426.

22.

22. Leaver DD , Swann PF , and Magee PN (1969). The induction of tumours in the rat by a single oral dose of N-nitrosomethylurea. Brit. J. Cancer 23:177–187.

23.

23. Lijinsky W (1982). Carcinogenesis studies with nitrosocimetidine. In: Banbury Report: Nitrosamines and Human Cancer, PN Magee (ed). Cold Spring Harbor Laboratory 12: 397–401.

24.

24. Lijinsky W and Taylor HW (1976). Carcinogenesis in Sprague-Dawley rats of N-nitroso-N-alkylcarbamate esters. Cancer Lett 1:275–279.

25.

25. Lijinsky W and Reuber MD (1984). Comparison of nitrosocimetidine with nitrosomethylnitroguanidine in chronic feeding tests in rats. Cancer Res. 44:447–449.

26.

26. Mirvish SS (1975). Formation of N-nitroso compounds. Chemistry, kinetics, and in vivo occurrence. Toxicol. Appl. Pharmacol. 31:325–351.

27.

27. Ogiu T , Nakadate M , Furuta K , Maekawa A , and Odashima S (1977). Induction of tumors of peripheral nervous system in female Donryu rats by continuous oral administration of 1-methyl-1-nitrosourea. Gann 68:491–498.

28.

28. Pool BL , Eisenbrand G , and Schmähl D (1979). Biological activity of nitrosated cimetidine. Toxicology 15:69–72.

29.

29. Reed PI , Cassell PG , and Walters CL (1979). Gastric cancer in patients who have taken cimetidine. Lancet i: 1234–1235.

30.

30. Schmähl D and Thomas C (1962). Die akute Vergiftung der Ratte mit Nitrosomethylurethan nach oraler Applikation. Arzneim.-Forsch. 12:585–587.

31.

31. Schoental R and Magee PN (1962). Induction of squamous carcinoma of the lung and of the stomach and esophagus by diazomethane and N-methyl-N-nitroso-urethane, respectively. Brit. J. Cancer 16:92–100.

32.

32. Schoental R and Bensted JPM (1969). Gastro-intestinal tumours in rats and mice following various routes of administration of N-methyl-N-nitroso-N'-nitroguanidine and N-ethyl-N-nitroso-N'-nitroguanidine. Brit. J. Cancer 23:757–764.

33.

33. Schwarz M , Hummel J , and Eisenbrand G (1980). Induction of DNA strand breaks by nitrosocimetidine. Cancer Lett. 10:223–228.

34.

34. Stekar J and Gimmy J (1980). Induction of lung tumours in rats by i.v. injection of N-methyl-N'-Nitro-N-nitrosoguanidine. Europ. J. Cancer 16:395–400.

35.

35. Sugimura T and Fujimura S (1967). Tumour production in glandular stomach of rat by N-methyl-N'-nitro-N-nitrosoguanidine. Nature 216:943–944.

36.

36. Swann PF and Magee PN (1968). Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methane-sulphonate. Biochem. J. 110:39–47.

37.

37. Taylor TV , Lee D , Howatson AG , Anderson J , and MacLeod IB (1979). Gastric cancer in patients who have taken cimetidine. Lancet i: 1235–1236.

38.

38. Weiss JF , Paoletti EG , Paoletti P , Schiffer D , and Fabiani A (1970). Occurrence of desmosterol in tumors of the nervous system induced in the rat by nitrosourea derivatives. Cancer Res. 30:2107–2109.