Effects of chronic ethanol consumption on the metabolism and carcinogenicity of N'-nitrosonornicotine in F344 rats.

The effects of chronic ethanol consumption on the carcinogenicity and metabolism of N'-nitrosonornicotine (NNN) in male F344 rats have been investigated. Groups of 26 to 30 rats were maintained on either a control liquid diet (Groups 1, 3, and 5) or an ethanol-containing liquid diet (Groups 2, 4, and 6) for 4 weeks prior to and during treatment with NNN. The carcinogen was injected s.c. (10 mg/kg, Groups 3 and 4) three times weekly or added to the liquid diet (17.5 mg/liter, Groups 5 and 6). The total dose was 1 mmol of NNN per rat. Control rats (Groups 1 and 2) received s.c. injections of 0.9% NaCl solution. The nasal mucosa was the main target tissue of NNN in Groups 3 and 4, but both the nasal mucosa and esophagus were major target tissues in Groups 5 and 6. In rats treated s.c. with NNN (Groups 3 and 4), ethanol consumption had no effect on the distribution and incidence of nasal cavity tumors. In rats treated with NNN added to the control liquid diet or to the ethanol-containing liquid diet, the number of tumors of the nasal cavity was 18 in Group 5 and 26 in Group 6 (p less than 0.05). In contrast, the number of rats with esophageal tumors was 25 in Group 5 and 20 in Group 6 (p less than 0.05). The effects of ethanol on the enzyme system which activates NNN were studied in rats which had been maintained on an ethanol-containing liquid diet for 4 weeks. Explants of nasal mucosae, lingual mucosae, esophagi , and livers were cultured in vitro with NNN. Nasal mucosae of ethanol-consuming rats had a 1.5-fold higher (p less than 0.05) alpha-carbon-hydroxylating activity than did those of control rats. Activating enzymes in the lingual mucosae, esophagi , and livers were not induced by ethanol. The results show that the increased susceptibility of the rat nasal mucosa to the carcinogenic effects of NNN added to an ethanol-containing diet could be due in part to an induction of activating enzymes by ethanol. However, since chronic ethanol consumption had no apparent effect on the incidence of nasal cavity tumors in rats treated by s.c. injection of NNN, factors other than enzyme induction are important in determining the effects of ethanol on NNN carcinogenicity.