Carcinogenesis, Vol 19, 933-937, Copyright © 1998 by Oxford University Press
S Ivankovic, J Seibel, D Komitowski, B Spiegelhalder, R Preussmann and M Siddiqi
Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-
nitroso compounds obtained from in vitro nitrosation of caffeidine, a
hydrolysis product of caffeine present in a typically made and widely
consumed tea from Kashmir (India), a high incidence area of esophageal and
stomach cancer. The chemical synthesis, in vitro metabolic studies and
mutagenicity of the compounds has been previously reported. DNC, a
nitrosamide is highly mutagenic both with and without metabolic activation
whereas MNC, like several other aromatic asymmetric nitrosamines, does not
exhibit genotoxic or mutagenic properties. We now report the results of the
first carcinogenicity experiments on chronic oral administration of these
compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and
230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages
were the first symptoms of intoxication observed after 2 days for both the
compounds. All three dose groups of MNC treated rats showed localization of
tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours
were histologically diagnosed as neuroepitheliomas of the olfactory
epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell
carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal
cavity were observed in the untreated controls. DNC, in contrast, induced
squamous cell carcinoma of forestomach in 100% animals at low and high
doses, of which nearly half the tumours metastasized predominantly into the
peritoneum. No forestomach tumours were seen in the untreated controls. The
data presented here clearly show the potential for induction of malignant
tumours and distinct organ- specificity by MNC and DNC in rats, and support
the postulate that a chronic exposure to these compounds may provide a
carcinogenic risk for high incidence of gastrointestinal cancers in
Kashmir.
ARTICLES
Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats
Division of Perinatal Toxicology, German Cancer Research Center Heidelberg.
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