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.
