Center for Global Health Faculty

Professor

Academic Degrees

• PhD

Departmental Affiliation

• Name:

  Environmental Health Sciences

  Affiliation Type:

  Primary

  Division:

  Toxicology

• Name:

  Biochemistry and Molecular Biology

  Affiliation Type:

  Joint

Departmental Address

Contact Information

Email:

tkensler+jhsph.edu

Phone:

410-955-1292

Fax:

410-955-0116

Link:

SciVal Experts Research Profile

Research and Professional Experience

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.

Keywords

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

Honors and Awards

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)

2010 Friendship Award, Jiangsu Province, PRC

2011 National Friendship Award, Beijing, People’s Republic of China

Selected Publications

Kensler, T.W., Ng, D., Carmella, S.G., Chen, M., Jacobson, L.P., Muñoz, A., Egner,  P.A., Chen, J.G., Qian, G.S., Chen, T.Y., Fahey, J.W., Talalay, P., Groopman, J.D., Yuan, J.M. and Hecht, S.S. (2012)  Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis 33: 101-107.

Agyeman, A., Chaerkady, R., Shaw, P., Davidson, N.E., Visvanathan, K., Pandey, A., and Kensler, T.W. (2011) Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res. Treat., in press.

Egner, P.A., Chen, J.G., Wang, J.B., Wu, Y., Sun, Y.  Lu, J.H., Zhu, J, Zhang, Y.H., Chen, Y.S., Friesen, M.D., Jacobson, L.P., Muñoz, A., Ng, D., Qian, G.S., Zhu, Y.R., Chen, T.Y., Botting, N.P., Zhang, Q.Z., Fahey, J.W., Talalay, P., Groopman, J.D., Kensler, T.W. (2011) Bioavailability of sulforaphane from two broccoli sprout beverages: Results of a short term, cross-over clinical trial in Qidong, China. Cancer Prev. Res. 4: 384-395.

Kensler, T.W., Roebuck, B.D., Wogan, G.N. and Groopman, J.D. (2011) Aflatoxin: A 50 year odyssey of mechanistic and translational toxicology. Toxicol. Sci., 120: 28-48.

Wakabayashi, N. Shin, S., Slocum, S., Agoston, E.S., Wakabayashi, J., Kwak, M.K., Misra, V., Biswal, S., Yamamoto, M. and Kensler, T.W. (2010) Regulation of Notch1 signaling by Nrf2: implications for tissue regeneration. Science Signaling 3: ra52.

Malhotra, D., Portales-Casamar, E., Singh, A., Srivastava, S., Arenillas, D., Happel, C., Shyr, C., Wakabayashi, N., Kensler, T.W., Wasserman, W.W. and Biswal, S. (2010) ChIP-Seq profiling and network analysis of Nrf2 reveals a direct role in a cell survival response. Nucl. Acids Res. 38: 5718-5734.

Wakabayashi, N., Slocum, S.L., Skoko, J.L., Shin, S. and Kensler, T.W. (2010) When NRF2 talks, who’s listening? Antioxidant & Redox Signaling 13: 1649-1663.

Kensler, T.W. and Wakabayashi, N. (2010) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31: 90-99.

Kensler, T.W. and Groopman, J.D. (2009) Is it time for microdosing trials to advance chemoprevention of environmental carcinogenesis? Cancer Prev. Res. 2: 1003-1007.

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 30: 1024-1031.

Shin, S., Wakabayashi, J., Yates, M., Wakabayashi, N., Dolan, P.M., Aja, S.M., Liby, K.T., Sporn, M.B., and Kensler, T.W. (2009) Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide. Europ. J. Pharmacology 620: 138-144.

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.

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.

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.

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.