Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats

Emerich S. Fiala, Cathy Joseph, Ock Soon Sohn, Karam El-Bayoumy, Bandaru S. Reddy

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Abstract

Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23% corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which docs not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of |14C] AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in |14C|AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of |14C| AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43%, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.

Original languageEnglish (US)
Pages (from-to)2826-2830
Number of pages5
JournalCancer Research
Volume51
Issue number11
StatePublished - Jan 1 1991

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Azoxymethane
Inbred F344 Rats
Colon
Carcinogenesis
Diet
Liver Microsomes
formic acid
Liver
benzyl selenocyanate
Organoselenium Compounds
Enzyme Induction
Corn Oil
DNA
Alkylation
DNA Methylation
Hydroxylation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Fiala, Emerich S. ; Joseph, Cathy ; Soon Sohn, Ock ; El-Bayoumy, Karam ; Reddy, Bandaru S. / Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats. In: Cancer Research. 1991 ; Vol. 51, No. 11. pp. 2826-2830.
@article{e42ebaaaa719491aa4391cf0a44dc0eb,
title = "Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats",
abstract = "Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23{\%} corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which docs not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of |14C] AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in |14C|AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of |14C| AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43{\%}, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.",
author = "Fiala, {Emerich S.} and Cathy Joseph and {Soon Sohn}, Ock and Karam El-Bayoumy and Reddy, {Bandaru S.}",
year = "1991",
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Fiala, ES, Joseph, C, Soon Sohn, O, El-Bayoumy, K & Reddy, BS 1991, 'Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats', Cancer Research, vol. 51, no. 11, pp. 2826-2830.

Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats. / Fiala, Emerich S.; Joseph, Cathy; Soon Sohn, Ock; El-Bayoumy, Karam; Reddy, Bandaru S.

In: Cancer Research, Vol. 51, No. 11, 01.01.1991, p. 2826-2830.

Research output: Contribution to journalArticle

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T1 - Mechanism of Benzylselenocyanate Inhibition of azoxymethaneinduced Colon Carcinogenesis in F344 Rats

AU - Fiala, Emerich S.

AU - Joseph, Cathy

AU - Soon Sohn, Ock

AU - El-Bayoumy, Karam

AU - Reddy, Bandaru S.

PY - 1991/1/1

Y1 - 1991/1/1

N2 - Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23% corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which docs not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of |14C] AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in |14C|AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of |14C| AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43%, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.

AB - Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23% corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which docs not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of |14C] AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in |14C|AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of |14C| AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43%, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.

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