Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat

Sidney S. Mirvish, Dennis D. Weisenburger, Steven Heye Hinrichs, Jeannetta Nickols, Connie Hinman

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-N-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC-Wistar rats were injected three times i.p. with 25mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated 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 necropsied. 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 treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 ± 0.08 in the MNAN alone group and 0.50 ± 0.14 in the MNAN + ethanol + catechol group. 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 esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P=0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 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 formation was significantly (P<0.05) reduced in the esophagus of rats given ethanol + catechol and in the liver of rats given catechol. Because the formation of 2- to 4-HO-MNAN in the esophagus may reflect that of 1-HO-MNAN, which methylates DNA and probably initiates tumorigenesis, the co-carcinogenicity of ethanol + catechol was unlikely to be due to increased esophageal α-hydroxylation of MNAN.

Original languageEnglish (US)
Pages (from-to)883-887
Number of pages5
JournalCarcinogenesis
Volume15
Issue number5
DOIs
StatePublished - May 1 1994

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Carcinogenesis
Ethanol
Esophagus
Papilloma
Guaiacol
Carcinoma
Drinking Water
catechol
Diet
Neoplasms
Liver
Hydroxylation
Smoke
Tobacco Products
Alcohol Drinking
Carcinogens
Wistar Rats
Squamous Cell Carcinoma
Smoking
Water

ASJC Scopus subject areas

  • Cancer Research

Cite this

Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat. / Mirvish, Sidney S.; Weisenburger, Dennis D.; Hinrichs, Steven Heye; Nickols, Jeannetta; Hinman, Connie.

In: Carcinogenesis, Vol. 15, No. 5, 01.05.1994, p. 883-887.

Research output: Contribution to journalArticle

Mirvish, Sidney S. ; Weisenburger, Dennis D. ; Hinrichs, Steven Heye ; Nickols, Jeannetta ; Hinman, Connie. / Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat. In: Carcinogenesis. 1994 ; Vol. 15, No. 5. pp. 883-887.
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abstract = "Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-N-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC-Wistar rats were injected three times i.p. with 25mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated 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 necropsied. 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 treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 ± 0.08 in the MNAN alone group and 0.50 ± 0.14 in the MNAN + ethanol + catechol group. 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 esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P=0.06). Forestomach papillomas occurred in 22{\%} of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 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 formation was significantly (P<0.05) reduced in the esophagus of rats given ethanol + catechol and in the liver of rats given catechol. Because the formation of 2- to 4-HO-MNAN in the esophagus may reflect that of 1-HO-MNAN, which methylates DNA and probably initiates tumorigenesis, the co-carcinogenicity of ethanol + catechol was unlikely to be due to increased esophageal α-hydroxylation of MNAN.",
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T1 - Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat

AU - Mirvish, Sidney S.

AU - Weisenburger, Dennis D.

AU - Hinrichs, Steven Heye

AU - Nickols, Jeannetta

AU - Hinman, Connie

PY - 1994/5/1

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N2 - Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-N-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC-Wistar rats were injected three times i.p. with 25mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated 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 necropsied. 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 treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 ± 0.08 in the MNAN alone group and 0.50 ± 0.14 in the MNAN + ethanol + catechol group. 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 esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P=0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 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 formation was significantly (P<0.05) reduced in the esophagus of rats given ethanol + catechol and in the liver of rats given catechol. Because the formation of 2- to 4-HO-MNAN in the esophagus may reflect that of 1-HO-MNAN, which methylates DNA and probably initiates tumorigenesis, the co-carcinogenicity of ethanol + catechol was unlikely to be due to increased esophageal α-hydroxylation of MNAN.

AB - Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-N-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC-Wistar rats were injected three times i.p. with 25mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated 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 necropsied. 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 treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 ± 0.08 in the MNAN alone group and 0.50 ± 0.14 in the MNAN + ethanol + catechol group. 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 esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P=0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 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 formation was significantly (P<0.05) reduced in the esophagus of rats given ethanol + catechol and in the liver of rats given catechol. Because the formation of 2- to 4-HO-MNAN in the esophagus may reflect that of 1-HO-MNAN, which methylates DNA and probably initiates tumorigenesis, the co-carcinogenicity of ethanol + catechol was unlikely to be due to increased esophageal α-hydroxylation of MNAN.

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