Phenylbutyl isoselenocyanate modulates phase I and II enzymes and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone-induced DNA adducts in mice

Melissa A. Crampsie, Nathan Jones, Arunangshu Das, Cesar Aliaga, Dhimant Desai, Philip Lazarus, Shantu Amin, Arun K. Sharma

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Abstract

Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.

Original languageEnglish (US)
Pages (from-to)1884-1894
Number of pages11
JournalCancer Prevention Research
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2011

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Glucuronosyltransferase
DNA Adducts
Glutathione Transferase
Lung Neoplasms
Protein Isoforms
Lung
Enzymes
Isothiocyanates
Liver
Structure-Activity Relationship
Selenium
Cytochrome P-450 Enzyme System
Tobacco
Carcinogenesis
Smoking
Diet
Messenger RNA
Serum
Research
ISC-4 compound

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Phenylbutyl isoselenocyanate modulates phase I and II enzymes and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone-induced DNA adducts in mice",
abstract = "Lung cancer remains one of the most preventable forms of cancer with about 90{\%} of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.",
author = "Crampsie, {Melissa A.} and Nathan Jones and Arunangshu Das and Cesar Aliaga and Dhimant Desai and Philip Lazarus and Shantu Amin and Sharma, {Arun K.}",
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T1 - Phenylbutyl isoselenocyanate modulates phase I and II enzymes and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone-induced DNA adducts in mice

AU - Crampsie, Melissa A.

AU - Jones, Nathan

AU - Das, Arunangshu

AU - Aliaga, Cesar

AU - Desai, Dhimant

AU - Lazarus, Philip

AU - Amin, Shantu

AU - Sharma, Arun K.

PY - 2011/11/1

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N2 - Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.

AB - Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.

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