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The effect of N-nitroso-2-methoxy-2,6-dimethylmorpholine on endocrine and exocrine pancreas of Syrian hamsters
Abstract:
N-Nitroso-2-methoxy-2,6-dimethylmorpholine (MeNDMM), a cyclic derivative of the proposed proximate pancreatic carcinogen N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), is shown to have an almost selective cytotoxic effect on pancreatic beta-cells when a single high dose is given to Syrian hamsters. Hence in this aspect its effect is comparable to that of streptozotocin, which has a glucose moiety similar to the MeNDMM structure. However, contrary to the effect of streptozotocin, low single (subdiabetogenic) doses of MeNDMM led to the development of pancreatic ductular and mixed ductular-insular neoplasms; only 1 animal also had islet cell adenoma. It therefore seems that MeNDMM possesses an affinity for both endocrine and exocrine pancreatic tissue. Other target tissues of MeNDMM were the forestomach, intra- and extrahepatic bile ducts, liver, kidneys and vagina. The tumors of these organs appeared in various incidences, partially in relation to dose and/or survival time. The possible mechanisms of the MeNDMM effect upon the endocrine and the exocrine pancreas is discussed.
Insights
N-Nitroso-2-methoxy-2,6-dimethylmorpholine (MeNDMM) selectively targets pancreatic beta-cells at high doses. Low doses of MeNDMM induce pancreatic ductular and mixed neoplasms, indicating effects on both endocrine and exocrine pancreas.
Area of Science:
- Toxicology
- Carcinogenesis
- Endocrinology
Background:
- N-Nitroso-2-methoxy-2,6-dimethylmorpholine (MeNDMM) is a cyclic derivative of N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP).
- Streptozotocin, a known pancreatic carcinogen, shares structural similarities with MeNDMM.
Purpose of the Study:
- To investigate the cytotoxic and carcinogenic effects of MeNDMM on pancreatic tissue in Syrian hamsters.
- To compare the effects of MeNDMM with streptozotocin on pancreatic beta-cells.
Main Methods:
- Administration of single high and low doses of MeNDMM to Syrian hamsters.
- Histopathological examination of pancreatic and other target tissues for cytotoxic and neoplastic changes.
Main Results:
- High doses of MeNDMM exhibited selective cytotoxicity towards pancreatic beta-cells, similar to streptozotocin.
- Low doses of MeNDMM induced pancreatic ductular and mixed ductular-insular neoplasms, with one case of islet cell adenoma.
- MeNDMM also targeted other organs, including the forestomach, bile ducts, liver, kidneys, and vagina, with tumor incidence related to dose and survival time.
Conclusions:
- MeNDMM demonstrates a dual effect on the pancreas, acting both as a cytotoxic agent for beta-cells and an inducer of neoplasms in both endocrine and exocrine tissues.
- MeNDMM possesses carcinogenic potential for multiple organs beyond the pancreas.