Many epidemiological studies provide convincing evidence for an inverse relation between the quantities of fruit and vegetables consumed and the risk of developing cancer. The Cruciferae (a vegetable family that includes broccoli, cabbage, cauliflower) play a prominent role in protection. These protective effects cannot be ascribed to a single mechanism. Nevertheless, extracts of many edible plants raise Phase 2 detoxication enzymes (e.g. glutathione transferases) in animals cells, and contain minor chemical components that are known Phase 2 enzyme inducers. Certain cultivars of Cruciferous vegetables, raised under strictly defined conditions are extremely rich in inducer activity. Large quantities of these plants will be developed in Project 1. Limited information indicates that nearly all of the inducer activity in these plants is attributable to their content of isothiocyanates an glucosinolate (biosynthetic precursors of isothiocyanates). It is the overall goal of this project to evaluate the biological properties of these plants in humans.
Aim 2. 1 is concerned with devising noninvasive methods for assessing the functional capacity of glutathione transferases (a Phase 2 enzyme) in humans. By administering test doses of an isothiocyanate (allyl isothiocyanate which can be easily and safety given in the form of horseradish), and taking advantage of the fact that isothiocyanates are rapidly and almost exclusively converted in high yield to N-acetylcysteine conjugates (dithiocarbamates) which are excreted in the urine. Glutathione transferases play a critical, and possibly rate-limiting, role in these conversions. The dithiocarbamates are easily quantitated by a cyclocondensation reaction developed for these purposes.
Aim 2. 2 seeks to answer the question to what extent glucosinolates (which are not inducers per se) are converted in the human body to isothiocyanates which are Phase 2 enzyme inducers.
In Aim 2. 3 human volunteers will be fed the aforementioned plants that are rich in inducer activity and the success of the proposed strategy will be evaluated by measuring the glutathione transferase activities, by methods developed in Aim 2.1. These experiments will provide information on whether such individuals can be expected to detoxify carcinogens and other electrophiles more rapidly and be protected against the toxic and neoplastic effects of these substances.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA044530-11
Application #
6269279
Study Section
Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cho, Hye-Youn; Reddy, Sekhar P; Debiase, Andrea et al. (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med 38:325-43
Guyton, Kathryn Z; Kensler, Thomas W; Posner, Gary H (2003) Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev 61:227-38
Peleg, Sara; Posner, Gary H (2003) Vitamin D analogs as modulators of vitamin D receptor action. Curr Top Med Chem 3:1555-72
Kensler, Thomas W; Egner, Patricia A; Wang, Jin-Bing et al. (2002) Strategies for chemoprevention of liver cancer. Eur J Cancer Prev 11 Suppl 2:S58-64
Dinkova-Kostova, A T (2002) Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic enzymes. Mini Rev Med Chem 2:595-610
Posner, Gary H; Halford, Bethany A; Peleg, Sara et al. (2002) Conceptually new low-calcemic oxime analogues of the hormone 1 alpha,25-dihydroxyvitamin D(3): synthesis and biological testing. J Med Chem 45:1723-30
Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26:175-82
Cho, Hye-Youn; Jedlicka, Anne E; Reddy, Sekhar P M et al. (2002) Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am J Respir Cell Mol Biol 26:42-51
Posner, Gary H; Northrop, John; Paik, Ik-Hyeon et al. (2002) New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorg Med Chem 10:227-32
Pereira, Fernanda Maria Valente; Rosa, Eduardo; Fahey, Jed W et al. (2002) Influence of temperature and ontogeny on the levels of glucosinolates in broccoli (Brassica oleracea Var. italica) sprouts and their effect on the induction of mammalian phase 2 enzymes. J Agric Food Chem 50:6239-44

Showing the most recent 10 out of 122 publications