EFFECT OF CATECHOL AND ETHANOL WITH AND WITHOUT METHYLAMYLNITROSAMINEON ESOPHAGEAL CARCINOGENESIS IN THE RAT

Alcohol consumption and cigarette smoking are synergistic etiologic fa ctors for squamous cell carcinoma of the esophagus in Western countrie s. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-n-amylnitrosamine (MNAN) for esophagea l tumors in rats, when it was given in the diet. Here we tested whethe r the inclusion of ethanol in a similar system had an additional promo ting effect on esophageal carcinogenesis. Male MRC - Wistar rats were injected three times i.p. with 25 mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treat ed for life with 10% ethanol and 0.2% catechol in the drinking water, starting at 6 weeks of age. One or more test chemicals were omitted in other groups. The rats were maintained until they died and were necro psied. The number of esophageal papillomas/rat was 2.18 +/- 0.36, 4.27 +/- 0.53, 2.54 +/- 0.48 and 3.21 +/- 0.52 (mean +/- SE) in groups tre ated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MN AN + catechol, respectively. Esophageal carcinomas showed a similar tr end, with the number of carcinomas/rat equal to 0.23 +/- 0.08 in the M NAN alone group and 0.50 +/- 0.14 in the MNAN + ethanol + catechol gro up. Tumor multiplicities for the esophageal papillomas and carcinomas were significantly (P < 0.05) greater in the MNAN + ethanol + catechol group than in the MNAN group. These findings indicate that, in the es ophagus, catechol alone was not significantly co-carcinogenic with MNA N when it was given in the drinking water (unlike when given in the di et in our previous study), but that ethanol + catechol given in the wa ter was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + ca techol without MNAN developed esophageal papillomas, as compared to ze ro incidence in untreated controls (P = 0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumo r induction, ethanol and catechol were co-carcinogenic with MNAN and a ppeared to be tumorigenic when given without MNAN. Ethanol and catecho l could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feedi ng these compounds for 5-7 weeks separately or together was examined o n 2-, 3-, 4- and 5-hydroxy-MNAN (HO-MNAN) production from MNAN by the esophagus and liver slices from freshly killed rats. Total HO-MNAN for mation was significantly (P < 0.05) reduced in the esophagus of rats g iven ethanol + catechol and in the liver of rats given catechol. Becau se the formation of 2- to 4-HO-MNAN in the esophagus may reflect that of 1-HO-MNAN, which methylates DNA and probably initiates tumorigenesi s, the co-carcinogenicity of ethanol + catechol was unlikely to be due to increased esophageal alpha-hydroxylation of MNAN.