CAFFEINE-DERIVED N-NITROSO COMPOUNDS - V - CARCINOGENICITY OF MONONITROSOCAFFEIDINE AND DINITROSOCAFFEIDINE IN BD-IX RATS

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-ni troso compounds obtained from in vitro nitrosation of caffeidine, a hy drolysis product of caffeine present in a typically made and widely co nsumed tea from Kashmir (India), a high incidence area of esophageal a nd 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 activ ation whereas MNC, like several other aromatic asymmetric nitrosamines , does not exhibit genotoxic or mutagenic properties. We now report th e results of the first carcinogenicity experiments on chronic oral adm inistration of these compounds in BD-IX rats. The acute LD50 of MNC an d DNC were about 1300 and 230 mg/kg b.w., respectively, Lung oedema an d gastrointestinal haemorrhages were the first symptoms of intoxicatio n 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 dia gnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal ca vity in the ratio of 3:1, No tumours of the nasal cavity were observed in the untreated controls, DNC, in contrast, induced squamous cell ca rcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneu m. No forestomach tumours were seen in the untreated controls. The dat a presented here clearly show the potential for induction of malignant tumours and distinct organ-specificity by MNC and DNC in rats, and su pport the postulate that a chronic exposure to these compounds may pro vide a carcinogenic risk for high incidence of gastrointestinal cancer s in Kashmir.