Isothiocyanates are effective and versatile chemopreventative agents in many animal models due to their ability to inhibit metabolic activation of carcinogens and/or induce phase II enzymes for detoxification. Studies have recently shown that, like the parent compounds, the thiol conjugates of isothiocyanates inhibited cytochrome P450 enzymes and induced glutathione transferases, and are inhibitory against the A/J mouse lung tumorigenesis induced by tobacco nitrosamine 4-(methylnitrosamino)-1(3- pyridyl)-1 butanone. These findings are interesting because thiol conjugation constitutes a major metabolic route to detoxify isothiocyanates via the mercapturic acid pathway. These results not only reveal how isothiocyanates may work as inhibitors in vivo, they also suggest that the less toxic conjugates may be promising candidates to place isothiocyanates as chemopreventative agents. Our main hypothesis is that the thiol conjugates, as a transport form, serves as a depot of isothiocyanate which slowly releases the parent compound and thiol via a dissociation mechanism. The purpose of this application is to explore the potential of the thiol conjugates as chemopreventative agents in lung tumorigenesis by carrying out the following studies:
Aim 1, we will study the role of conjugate dissociation in cytochrome P450 enzyme inhibition;
Aim 2, we will determine the tissue distribution, in vivo metabolism, and toxicity of the conjugates;
Aim 3, we will examine the effects of isothiocyanates and conjugates on lung tumorigenesis induced by tobacco carcinogens;
Aim 4, we will compare the metabolism of the conjugates and their parent compounds in rodents and humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA046535-13S1
Application #
6396784
Study Section
Project Start
2000-02-01
Project End
2001-01-31
Budget Start
Budget End
Support Year
13
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Stoner, Gary D; Wang, Li-Shu; Chen, Tong (2007) Chemoprevention of esophageal squamous cell carcinoma. Toxicol Appl Pharmacol 224:337-49
Hudson, Tamaro S; Stoner, Gary D; Morse, Mark A et al. (2005) Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion. Toxicol Lett 155:427-36
Liston, Beth W; Nines, Ronald; Carlton, Peter S et al. (2003) Perillyl alcohol as a chemopreventive agent in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Cancer Res 63:2399-403
Carlton, Peter S; Gopalakrishnan, Rajaram; Gupta, Ashok et al. (2002) Piroxicam is an ineffective inhibitor of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus. Cancer Res 62:4376-82
Gopalakrishnan, Rajaram; Gupta, Ashok; Carlton, Peter S et al. (2002) Functional role of cytochrome p-450 2a3 in N-nitrosomethylbenzylamine metabolism in rat esophagus. J Toxicol Environ Health A 65:1077-91
Gupta, A; Nines, R; Rodrigo, K A et al. (2001) Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat. J Natl Cancer Inst 93:990-8
Hudson, T S; Carlton, P S; Gupta, A et al. (2001) Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate. Cancer Lett 162:19-26
Liston, B W; Gupta, A; Nines, R et al. (2001) Incidence and effects of Ha-ras codon 12 G-->A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus. Mol Carcinog 32:1-8
Boone, C W; Stoner, G D; Bacus, J V et al. (2000) Chemoprevention with theaflavins of rat esophageal intraepithelial neoplasia quantitatively monitored by image tile analysis. Cancer Epidemiol Biomarkers Prev 9:1149-54
Chung, F L; Jiao, D; Getahun, S M et al. (1998) A urinary biomarker for uptake of dietary isothiocyanates in humans. Cancer Epidemiol Biomarkers Prev 7:103-8