Research interests in my laboratory focus on the biochemical and molecular mechanisms involved in the induction of cancer by chemicals to serve as a basis for the prevention, interruption or reversal of these processes in man. One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases and NAD(P)H:quinone reductase that facilitate the detoxication and elimination of carcinogens. Furthermore, animal studies indicate that induction of these cytoprotective enzymes is a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally-occurring and synthetic chemical agents. Our work utilizes animal and cell culture models to elucidate mechanisms of inhibition of aflatoxin hepatocarcinogenesis by dithiolethiones such as oltipraz, isothiocyanates such as sulforaphane and triterpenoids such as CDDO-Im. While induction of glutathione S-transferases clearly play an important role in chemoprevention of aflatoxin hepatocarcinogenesis, ongoing studies are seeking to identify additional genes induced by these agents. The Keap1-Nrf2 signaling pathway is activated by these classes of chemopreventive agents and leads to increased expression of genes that attenuate oxidative stress and inflammation among other actions. Their contributions to protection against carcinogenesis are under investigation.

A practical goal of our research has been to develop the tools to test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans. Hepatocellular carcinoma is the leading cause of cancer death in parts of Asia and Africa and may relate to hepatitis B virus infection and aflatoxin ingestion. Longitudinal surveys and prospective case-control studies in Qidong, P.R. China demonstrate consistent exposure of individuals in this region to aflatoxins and indicate a prime role for aflatoxin in the etiology of liver cancer, respectively. As a consequence, we have conducted clinical chemoprevention trials of oltipraz and other agents in Qidong. The initial randomized, placebo-controlled intervention of oltipraz demonstrated an increased excretion of aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of participants receiving oltipraz. This study highlights the general feasibility of inducing Nrf2-regulated enzymes in humans. Follow-up trials are evaluating more effective agents and are assessing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time and whether diminished incidence of liver cancer can be achieved in this high-risk population.

Environmental Health Sciences, chemical carcinogenesis, chemoprevention, hepatocarcinogenesis, reactive oxygen, antioxidants, enzyme induction, aflatoxin, oltipraz, chlorophyllin, sulforaphane, Keap1, Nrf2, triterpenoids

2007 AACR-American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention

2009 Society of Toxicology Translational Impact Award

2009 Golden Apple Award for Excellence in Teaching in Public Health Studies, Johns Hopkins University (undergraduates)

Yates, M.S., Tran, Q.T., Dolan, P.D., Osburn, W.O., Shin, S., McCulloch, C.C., Silkworth, J.B., Taguchi, K., Yamamoto, M., Williams, C.R., Liby, K.T., Sporn, M.B., Sutter, T.R., and Kensler, T.W. (2009) Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid treated mice. Carcinogenesis, in press.

Blackford, A., Parmigiani, G., Kensler, T.W., Wolfgang, C., Jones, S., Zhang, X-S., Parsons, D.W., Lin, J C-H., Leary, R.J., Eshleman, J.R., Goggins, M., Jaffee, E.M., Iacobuzio-Donahue, C.A., Maitra, A., Klein A., Cameron, J.L., Olino, K., Schulick, R., Winter, J., Vogelstein, B, Velculescu, V.E., Kinzler, K.W., and Hruban, R.H. (2009) Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 69:3681-3688.

Roebuck, B.D., Johnson, D.N., Sutter, C.H., Egner, P.A., Scholl, P.F., Baumgartner, J.J., Ware, N.M., Bodreddigari, S., Groopman, J.D., Kensler, T.W., and Sutter, T.R. (2009) Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat. Toxicological Sciences 109: 41-49.

Sussan, T.E., Rangasamy, T., Blake, D.J., Malhotra, D., El-Haddad, H., Bedja, D., Yates, M.S., Yamamoto , M., Liby, K.T., Sporn , M.B., Gabrielson, K.L., Champion , H.C., Tuder, R.M., Kensler, T.W. and Biswal, S. (2009) Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc. Natl. Acad. Sci. (USA) 106:250-255.

Egner, P.A., Kensler, T.W., Chen, J-G., Gange, S.J., Groopman, J.D. and Friesen, M.D. (2008) Quantitation of sulforaphane mercapturic acid pathway conjugates in human urine by high-performance liquid chromatrography and isotope-dilution tandem mass spectrometry. Chem. Res. Toxicol. 21: 1991-1996.

Bransfield, L.A., Rennie, A., Visvanathan, K., Odwin, S.A., Kensler, T.W., Yager, J.D., Friesen, M.D., and Groopman, J.D. (2008) Formation of novel oxidative estrogen guanine adducts and the detection by mass spectrometry of 4-hydroxyestradiol-N7-guanine in human urine. Chem. Res. Toxicol 21:1622-1630.

Liby, K., Yore, M.M., Roebuck, B.D., Baumgartner, K.J., Honda, T., Sundararjan, C., Yoshizawa, H., Gribble, G.W., Williams, C.R., Risingsong, R., Royce, D.B., Dinkova-Kostova, A.T., Stephenson, K.K., Egner, P.A., Yates, M.S., Groopman, J, Kensler, T.W. and Sporn, M.B. (2008) A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res. 68: 6727-6733.

Groopman, J.D., Kensler, T.W., and Wild, C.P. (2008) Protective interventions to prevent aflatoxin-induced carcinogenesis in developing countries. Ann. Rev. Public Health 29:187-203.

Osburn, W.O. and Kensler, T.W. (2008) Keap1-Nrf2: an adaptive response pathway for protection against environmental toxic insults. Mutation Res. 659: 31-39.

Bodreddigari, S., Jones, L.K., Egner, P.A., Groopman, J.D., Sutter, H., Roebuck, B.D., Guengrich, F.P., Kensler, T.W. and Sutter, T.R. (2008) Protection against aflatoxin B1-induced cytotoxicity by expression of cloned aflatoxin B1-aldehyde reductases, rat AKR7A1 and human AKR7A3. Chem. Res. Toxicol. 21: 1134-1142.

Osburn, W.O., Yates, M.S., Dolan, P.M., Chen, S., Liby, K.T., Sporn, M.B., Taguchi, K., Yamamoto, M. and Kensler, T.W. (2008) Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicological Sciences 104: 218-227.

Johnson, D.N., Egner, P.A., O’Brian, G.O., Glassbrook, N., Sutter, T.R., Roebuck, B.D., Payne, G.A., Kensler, T.W. and Groopman, J.D. (2008) Quantification of urinary aflatoxin B1 dialdehyde metaboltes formed by aflatoxin aldehyde reductase using isotope dilution tandem mass spectrometry. Chem. Res. Toxicol. 21:752-760.

Pearson, K.J., Lewis, K.N., Price, N.L., Chang, J.W., Perez, E., Cascajo, M.V., Tamashiro, K.L., Poosala, S., Bell, J.B., Kensler, T.W., Yamamoto, M., Egan, J.M., Longo, D.L., Ingram, D.K., Navas, P. and de Cabo, R. (2008) Nrf2 mediates cancer protection but not prolongevity by caloric restriction. Proc. Natl. Acad. Sci, USA 105:2325-2330.

Chu, H., Nie, L. and Kensler , T.W. (2008) A Bayesian approach estimating treatment effects on biomarkers containing zeros with detection limits. Statistics in Medicine 27: 2497-508.

Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G.H., Agoston, E.S., Yamamoto, M., and Kensler, T.W. (2007) NRF2 modulates AHR signaling: influence on adipogenesis. Molec. Cell. Biol. 27: 7188-7197.

Kensler, T.W., Wakabayashi, N., and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Ann. Rev. Pharmacol. Toxicol. 47: 89-116.

Cornblatt, B.S., Ye, L., Dinkova-Kostova, A.T., Erb, M., Fahey, J.W., Singh, N.K., Chen, A-s.A., Stierer, T., Garrett-Meyer, E., Argani, P., Davidson, N.E., Talalay, P., Kensler, T.W. and Visvanathan, K. (2007) Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis 28: 1485-1490.

Osburn, W.O., Karim, B., Dolan, P.M., Liu, G., Yamamoto, M., Huso, D.L. and Kensler, T.W. (2007) Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int. J. Cancer 121: 1883-1891.

Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, H., Kensler, T.W., and Yamamoto, M. (2006) Hepatocyte-specific deletion of the keap1 gene confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Comm. 339: 79-88.

Yates, M.S., Kwak, M-K., Egner, P.A., Groopman, J.D., Bodreddigari, S., Sutter, T.R., Baumgartner, K.J., Roebuck, B.D., Yore, M.M., Honda, T., Gribble, G.W., Sporn, M.B. and Kensler, T.W. (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 66: 2488-2494.

Kensler, T.W., Chen, J-G., Egner, P.A., Fahey, J.W., Jacobson, L.P., Stephenson, K.K., Ye, L., Coady, J.L., Wang, J-B., Wu, Y., Sun, Y., Zhang, Q-N., Zhang, B-C., Zhu, Y-R., Qian, G-S., Carmella, S.G., Hecht, S.S., Benning, L., Gange, S.J., Groopman, J.D. and Talalay, P. (2005) Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthene tetraols in a randomized clinical trial in He Zuo Township, Qidong, PRC. Cancer Epidemiol. Biomarkers Prev. 14:2605-2613.