The relationship between exposure to environmental and endogenous chemicals and risk of cancer and other diseases. Our approach utilizes chemical reactions, components of cells, cells in culture, and animal models for development of chemical biomarkers for application to human populations.
The Quantification of Human Exposure to Carcinogens. Some environmental chemicals pose risks to human health. The accurate assessment of these risks requires quantitative data on human exposure. Such data are currently estimated from measurements of the chemicals in air, water or food. Direct measurements in human blood, urine, or tissues have generally not been attempted, since the compounds involved are usually short-lived and present in low levels. We have developed an analytical approach for the quantitation of toxicologically significant compounds by monitoring their reaction products to human proteins. The proposed method is applicable to many carcinogens, mutagens, and other reactive chemicals. The results allow more accurate assessments of human risk, and more precise epidemiological investigations of the links, for example, between exposure to carcinogens and human cancer.
The basis of this research is as follows. Compounds such as carcinogens are toxic often because they react within the body to modify the genetic material (DNA). The same electrophiles that react with DNA also react with proteins. Since DNA is repaired and proteins are not, the protein serves as a template for carcinogen exposure. Measurement of protein adducts is therefore a useful approach for human biomonitoring and investigation of the effect of metabolic polymorphisms.
Detection of protein adducts in human requires analytical tools that are both sensitive and specific. Our laboratory specializes in the application of mass spectrometry and laser fluorescence methods to these problems.
Nitric oxide is formed by many types of cells in the body for the purpose of intercellular communication (brain, cardiovascular system) or as part of the immune or inflammatory response system (macrophages, endothelial cells). The chemistry of NO( in oxygenated biological systems is very complex both in number of chemical species and in a number of parallel and consecutive reactions. Damage to DNA in mammalian cells is caused by N2O3 which yields deaminated bases from adenine, cytosine, 5-methylcytosine, and guanine.
A second type of DNA damage occurs when O2-( is also present. In this case peroxynitrite forms rapidly and then following protonation undergoes homolytic scission to hydroxyl radical and NO2. Hydroxyl radical gives the spectrum of base changes and mutations normally associated in biological systems with the Fenton reaction. The focus of our research has been on the nature and extent of DNA damage in generator cells such as macrophages producing NO( and O2-( and in their target cells. The mutagenicity of NO( has been established in bacteria and human cells. In tissues undergoing an inflammatory reaction, both the infiltrating and resident cell populations produce a time-dependent mixture of nitrogen oxide radicals and oxygen radicals. These different radical species interact forming new reactive intermediates which may contribute to DNA damage. Although the flux of radicals per unit time is low, an inflammatory condition that continues for years becomes a significant risk factor for carcinogenic cell transformation. The relative contributions of various radical species to the carcinogenic process must be assessed through both chemical analysis of DNA and through genetic and molecular biological analysis of mutations in surviving exposed cells.
In our laboratory we are conducting research to understand these chemical processes in cells and animals with a goal of applying our results to human disease.
S.R. Tannenbaum and P.L. Skipper. 1994. Quantitative analysis of hemoglobin-xenobiotic adducts. In: Methods in Enzymology - Hemoglobins, Chp. XXX - Xenobiotic Adducts of Human Hemoglobin. J. Everse, et al., eds. Academic Press, pp. 625-632.
P. Vineis, H. Bartsch, N. Caporaso, A.M. Harrington, F. Kadlubar, M.T. Landi, C. Malaveille, P. Shields, P.L. Skipper, G. Talaska, and S.R. Tannenbaum. 1994. Genetically-based N-acetyltransferase metabolic polymorphisms and low-level environmental exposure to carcinogens. Nature 369, 154-156.
C.K. Soohoo, K. Singh, P.L. Skipper, R.R. Dasari and S.R. Tannenbaum. 1994. Characterization of benzo[a]pyrene anti-diol epoxide adducts to human histones. Chem. Res. Toxicol. 7, 134-138.
P.L. Skipper, X. Peng, C.K. SooHoo, and S.R. Tannenbaum. 1994. Protein adducts as biomarkers of human carcinogen exposure. Drug Metabolism Rev. 26, 111-124.
Y.-J. Surh, and S.R. Tannenbaum. 1994. Bioactivation of cyclopenta- an cyclohexafused polycyclic aromatic hydrocarbons via the formation of benzylic sulfuric acid esters. IN: Polycyclic Aromatic Compounds, Vol. 7, E. Cavalieri, et al., eds., pp. 83-90.
Y.-J. Surh and S.R. Tannenbaum. 1994. Activation of the maillard reaction product, 5-hydroxymethylfurfural to strong mutagens via allylic sulfonation and chlorination. Chem. Res. Toxicol. 7, 313-318.
W.G. Stillwell, R.J. Turesky, G.A. Gross, P.L. Skipper and S.R. Tannenbaum. 1994. Human urinary excretion of sulfamate and glucuronide conjugates of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Cancer Epidemiol., Biomarkers & Prev. 3, 399-405.
H. Ji, M.C. Yu, W.G. Stillwell, P.L. Skipper, R.K. Ross, B.E. Henderson, and S.R. Tannenbaum. 1994. Urinary excretion of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in white, black, and asian men in Los Angeles Country. Cancer Epidemiol., Biomarkers & Prev. 3, 407-411.
Y. Sahali, P.L. Skipper, and S. Tannenbaum. 1994. Metabolism of Benz[a]anthracene by human liver microsomes. Cancer Lett. 83, 299-303.
Y.-J. Surh, A. Liem, J. Miller, and S.R. Tannenbaum. 1994. 5-Sulfooxymethylfurfural as a possible ultimate mutagenic and carcinogenic metabolite of the Maillard reaction product 5-hydroxymethylfurfural. Carcinogenesis 15, 2375-2377.
C.C. Ozbal, I. Velic, C.K. SooHoo, P.L. Skipper, and S.R. Tannenbaum. 1994. Conservation of histone carcinogen adducts during replication: implications for long term molecular dosimetry. Cancer Res. 54, 5599-5601.
B.W. Day, P.L. Skipper, J. Zaia, K. Singh, and S.R. Tannenbaum. 1994. Enantiospecificity of covalent addict formation by benzo[a]pyrene anti-diol epoxide with human serum albumin. Chem. Res. Toxicol. 7, 829-835.
E.A. Carter, T.C. deRojas-Walker, S. Tamir, S.R.Tannenbaum, Y.-M. Yu, and R.G. Tompkins. 1994. Nitric oxide production is intensely and persistently increased in tissues by thermal injury. J. Biochem. 304, 201-204.
P.L. Skipper and S.R. Tannenbaum. 1994. Molecular dosimetry of aromatic amines in human populations. Environ. Health Perspectives 102 (Suppl. 6), 17-21.
R.J. Turesky, G.A. Gross, W.G. Stillwell, P.L. Skipper, and S.R. Tannenbaum. 1994. Species differences in metabolism of heterocyclic aromatic amines, human exposure and biomonitoring. Environ. Health Perspectives 102 (Suppl. 6), 47-51.
L. Castillo, M. Sanchez, J. Vogt, T.E. Chapman, T.C. deRojas-Walker, S.R. Tannenbaum, A.M. Ajami, and V.R. Young. 1995. Am. J. Phys. 268 (Endocrinol. Metab. 31): E360-E367.
S.R. Tannenbaum, S. Stillwell, H. Ji, P. Skipper, M. Yu, R. Ross, B. Henderson, R.J. Turesky, and G.A. Gross. 1995. MeIQx (2-amino-dimethylimidazo[4,5-f]quinoxaline): Metabolism in humans and urinary metabolites in human populations. IN: Heterocyclic Amines in Cooked Foods: Possible Human Carcinogens. Proc. of the International Symposium of the Princess Takamatsu Cancer Research Fund, (R.H. Adamson, et al., eds.), pp. 197-206, Princeton Scientific Publishing Co., Inc., Princeton, NJ.
T.C. deRojas-Walker, S. Tamir, H. Ji, J.S. Wishnok, and S.R. Tannenbaum. 1995. Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA. Chem. Res. Toxicol. 8, 473-477.
T. Nunoshiba, T. deRojas-Walker, S.R. Tannenbaum, and B. Demple. 1995. Roles of nitric oxide in inducible resistance of Escherichia coli to activated murine macrophages. Infect. Immun. 63, 794-798.
S.R. Tannenbaum and J.S. Wishnok. 1995. Genotoxicity of nitric oxide via nitrosative deamination of bases in DNA. IN: Biology of Nitric Oxide. (S. Moncada, M.A. Marletta, J.B. Hibbs, Jr. and E.A. Higgs, Editors), pp. 206-208, Portland Press, Ltd.
R.S. Lewis, S.R. Tannenbaum, and W.M. Deen. 1995. Kinetics of N-nitrosation in oxygenated nitric oxide solutions at physiological pH: role of nitrous anhydride and effects of phosphate and chloride. J. Am. Chem. Soc., 117, 3933-3939.
Y. Surh and S.R. Tannenbaum. 1995. Sulfotransferase-mediated activation of 7,8,9,10-tetrahydro-7-ol, 7,8-dihydrodiol, and 7,8,9,10-tetraol derivatives of benzo[a]pyrene. Chem. Res. Toxicol. 53, 1017-1022.
S.R. Tannenbaum, J.S. Wishnok, T.R. Walker, S. Tamir, and H. Ji. 1995. Overview of nitric oxide and nitric oxide/superoxide chemical interactions with DNA. Cancer Res. (in press).
C.D. Leaf and S.R. Tannenbaum. 1995. The role of dietary nitrate and nitrite in human cancer. IN: Nutrition and Cancer Prevention, R.R. Watson, ed., CRC Press, Chapter 17, (in press).
J. S. Wishnok, J.A. Glogowski, and S.R. Tannenbaum. 1995. Quantitation of nitrate, nitrite, and nitrosating agents. IN: Nitric Oxide, Lester Packer (editor), Methods in Enzymology Series, Academic Press, Inc. (in press).
S. Tamir, J.S. Wishnok, and S.R. Tannenbaum. 1995. DNA damage and genotoxicity by nitric oxide. IN: Nitric Oxide, Lester Packer (editor), Methods in Enzymology Series, Academic Press, Inc. (in press).
S. Tamir, T. deRojas-Walker, A. Gal, A.H. Weller, X. Li, J.G. Fox, G.N. Wogan, and S.R. Tannenbaum. 1995. Nitric oxide production in relation to spontaneous B cell lymphoma and myositis in SJL mice. Cancer Res. (in press).
M.M. Kurrek, L. Castillo, K.D. Block, S.R. Tannenbaum, and W.M. Zapol. 1995. Inhaled nitric oxide does not alter enotocin-induced nitric oxide synthase activity during perfusion of the isolated rat lung. J. Appl. Physiol. (in press).
J.S. Wishnok, S.R. Tannenbaum, S. Tamir, and T. deRojas-Walker. 1995. Endogenous formation of nitrate. Proc. of the International Workshop on Health Aspects of Nitrate and its Metabolites (Particularly Nitrite), Bilthoven, The Netherlands, 8-10 Nov., 1994 (in press).
S.R. Tannenbaum. 1995. Safety evaluation of inhaled nitric oxide. IN: Lung Biology in Health and Disease, Marcel Dekker, Inc., New York (in press).