Journal article
Phenylbutyl Isoselenocyanate Modulates Phase I and II Enzymes and Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induced DNA Adducts in Mice
Cancer prevention research (Philadelphia, Pa.), Vol.4(11), pp.1884-1894
11/2011
Handle:
https://hdl.handle.net/2376/100847
PMCID: PMC3208061
PMID: 21795424
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 based on naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In the present 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 (Cyp) 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 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 (NNK). These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.
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Details
- Title
- Phenylbutyl Isoselenocyanate Modulates Phase I and II Enzymes and Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induced DNA Adducts in Mice
- Creators
- Melissa A Crampsie - Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Nathan Jones - Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Arunangshu Das - Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Cesar Aliaga - Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Dhimant Desai - Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Philip Lazarus - Department of Public Health Sciences, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Shantu Amin - Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033Arun K Sharma - Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033
- Publication Details
- Cancer prevention research (Philadelphia, Pa.), Vol.4(11), pp.1884-1894
- Academic Unit
- Pharmaceutical Sciences, Department of
- Grant note
- R03 CA143999-01 || CA / National Cancer Institute : NCI R01 DE013158-01A1 || DE / National Institute of Dental and Craniofacial Research : NIDCR
- Identifiers
- 99900546642701842
- Language
- English
- Resource Type
- Journal article