Abstract
Dithiolethiones and other cancer chemopreventive agents inhibit the production of experimentally produced tumors by elevating the expression of several genes that encode for known cytoprotective enzymes1. Complementary DNA clones representing dithiolethione-inducible gene-1 (DIG-1*) were isolated from rat liver via differential hybridization screening2. The deduced amino acid sequence of DIG-1 was found to have 80% identity with the human liver enzyme leukotriene B4 (LTB4)-12-hydroxydehydrogenase (LTB4 DH)3,4. DIG-1, purified >400-fold from the liver of rats dosed with l,2-dithiole-3-dithiolethione (D3T), possessed an NADP+-dependent activity to convert LTB4 to 12-oxo-LTB4 similar to LTB4DH 3. The formation of 12-oxo- LTB4 by LTB4 DH is the first step in the catabolism of LTB4 4,5. Subsequent conversion of 12-oxo- LTB4 to 10,11-dihydro-12-oxo- LTB4 (Met I) and 10,11,14,15-tetrahyro- 12-oxo- LTB4 (Met II) by as yet unidentified reductases has been described in liver and kidney cytosolic preparations as shown in Fig. 16. These metabolic products of LTB4 have diminished pro-inflammatory capacities, such as enhancing the mobilization of intracellular calcium, putatively via antagonism of the LTB4 receptor7. Suppression of the pro-inflammatory actions of LTB4, such as stimulation of neutrophil chemotaxis and Superoxide anion generation, suggests that the catabolism of LTB4 is a cytoprotective process.
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Abbreviations
- BNF:
-
β-naphthoflavone
- D3T:
-
l,2-dithiole-3-thione
- DIG-1:
-
dithiolethione-inducible gene-1
- DS:
-
disulfiram
- EQ:
-
ethoxyquin
- 13-HODE:
-
13(S)-hydroxyoctadeco—9Z,13E-dienoic acid
- I3C:
-
indole-3-carbinol
- LTB4 :
-
leukotriene B4
- LTB4DH:
-
leukotriene B4 12-hydroxydehydrogenase
- OLT:
-
oltipraz [5-(2-pyrazinyl)-4-methyl-l,2-dithiole-3-thione]
- tBHQ:
-
tert-butylhydroquinone
References
Primia T. Sutter T.R. and Kensler T.W. Antioxidant-inducible genes Adv. Pharmacol. 38 293–328 1997
Primiano, T., Gastel, J.A., Kensler, T.W., and Sutter, T.R. Isolation of cDNAs representing dithiolethione-responsive genes, Carcinogenesis 17, 2297–2303 (1996).
Primiano, T., Li, Y., Kensler, T.W., Trush, M.A., and Sutter, T.R. Identification of dithiolethione-inducible gene-1 as leukotriene B4 12-hydroxydehydrogenase: Implications for chemoprevention, Carcinogenesis, in press.
Yokomizo, T., Izumi, T., Takahashi, T., Kasama, T., Kobayashi, Y., Sato, F., Taketani, Y., and Shimizu, T. Enzymatic inactivation of leukotriene B4 by a novel enzyme found in porcine kidney, J. Biol. Chem. 268, 18128–18135 (1993).
Wainwright S.L. and Powell W.S. Mechanism of the formation of dihydro metabolites of 12-hydroxyeicosaids J. Biol Chem. 266 20899–20906 1991
Powell, W.S., and Gravelle, F. Metabolism of leukotriene B4 to dihydro and dihydro-oxo products by porcine leukocytes, J. Biol. Chem. 263, 2170–2177 (1989).
Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., and Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis, Nature 387, 620–624 (1997).
Primiano, T., and Novak, R.F. Enhanced expression, purification, and characterization of a novel class alpha glutathione S-transferase isozyme appearing in rabbit hepatic cytosol following treatment with 4-picoline, Toxicol. Appl. Pharmacol. 112, 291–299 (1992).
Kensler, T.W., Groopman, J.D., Roebuck, B.D., and Curphey, T.J. In Huang, M-T. Osawa, T., Ho, C-T., and Rosen, R.T. (eds.) Food Phytochemicals for CancerPrevention I: Fruits and Vegetables. American Chemical Society, Washington D.C., pp. 154–163 (1994).
Demopoulos H. Pietronigro D.D. Seligman M.L. The development of secondary pathology with free radical reactions as a threshold mechanism J. Amer. Coll. Toxicol 2 173–184 1994
Ekbom, A., Helmick, C., Zack, M., and Adami, H-O. Ulcerative colitis and colorectal cancer: a population-based study, N. Engl. J. Med 323, 1228–1233 (1990).
Parsonnet J. Friedman G.D. Vandersteen D.P. Helicobacter pylori infection and the risk of gastric carcima N. Engl. J. Med 325 1127–1131 1991
Hagen, T.M., Huang, S., Curnutte, J., Fowler, P., Martinez, V., Wehr, C.M., Ames, B.N., Chisari, F.V. Extensive oxidative DNA damage in hepatocyres of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma, Proc. Natl. Acad. Sci. USA 91, 12808–12812 (1994).
Sharon, P., and Stenson, W.F. Enhanced synthesis of leukotirene B4 by colonic mucosa in inflammatory bowel disease, Gastroenterology 86, 453–460 (1984).
Li, Y., Ferrante, A., Poulos, A., and Harvey, D.P. Neutrophil oxygen radical generation: synergistic responses to tumor necrosis factor and mono/polyunsaturated fatty acids, J. Clin. Invest. 97, 1605–1609 (1996).
Cerutti P.A. Prooxidant states and tumor promotion. Science 227 375–381 1985
Trush, M.A., and Kensler, T.W. An overview of the relationship between oxidative stress and chemical carcinogenesis. Free Radical Biol. Med. 10, 201–209 (1991).
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Primiano, T., Kensler, T.W., Trush, M.A., Sutter, T.R. (1999). Induction of Leukotriene B4 Metabolism by Cancer Chemopreventive Agents. In: Honn, K.V., Marnett, L.J., Nigam, S., Dennis, E.A. (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 4. Advances in Experimental Medicine and Biology, vol 469. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4793-8_87
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DOI: https://doi.org/10.1007/978-1-4615-4793-8_87
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