The oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H 2 O 2 . Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects.
SUMMARY.-Six out of 120 rats fed dioxane in drinking water at levels of 0 75, 1.0, 1-4 or 1.8% developed carcinomas in the nasal cavity. Spontaneous tumors at this tissue localization have not been reported to occur in laboratory animals. The carcinomas were pre-eminently of epidermoid type with few adenocarcinomatous areas and epithelial papillomas. Four rats with carcinoma of the nasal cavity had hepatocellular carcinoma in addition.SPONTANEOUS tumors of the nasal cavity of laboratory animals have so far not been described. Herrold and Dunham (1963) reported that diethylnitrosamine (DEN) on intragastric feeding or on intra-tracheal instillation induced carcinomas of the ethmoid region of the nasal cavity in the Syrian hamster. Druckrey et al. (1964) reported that certain dialkyl nitrosamines (dimethyl-, methylallyl-, methylvinylnitrosamine) as well as several other nitroso compounds, such as nitrosomethylurea, nitrosomethylurethane, nitrosopiperazine and nitrosomorpholin induced in rats, on subcutaneous or intravenous injection, or on inhalation, large numbers of tumors in the nasal cavity. Tumors were also induced in the nasal cavity of mice by application of DEN on the skin of the back (Hoffman and Graffi, 1964). In all these experiments it was assumed that diazoalkane derivatives of the nitrosamines are the proximate carcinogens. Stewart et al. (1965) observed in rats which have ingested N,N'-2,7-fluorenylenbisacetamide an occasional animal with epidermoid or adenocarcinomas and with neuroepithelial tumors originating in the nasal cavity. In the following, carcinomas of the nasal cavity induced by dioxane are described.
MATERIALS AND METHODSFive groups of 30 male rats each (Charles River CD strain, random bred, Sprague-Dawley descendent 1950) two to three months old and weighing 110 to 230 g. at the beginning of the experiment were used. For the purpose of establishing the hepatic carcinogenic dose-response (to be published later), four groups of rats received in the drinking water 0-75 00, 1.00%, 1.40% or 1 80% of dioxane (Eastman Organic Chemicals No. 2144) for 13 months. One group served as control. On two occasions during the study, the average fluid consumption was determined for each group over a 3-day period. The rats were killed with ether at 16 months, or earlier if the nasal cavity tumors were clearly observable. On all animals complete autopsies were performed.
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