Carcinogenesis, Vol 19, 999-1005, Copyright © 1998 by Oxford University Press
T Primiano, Y Li, TW Kensler, MA Trush and TR Sutter
Cancer chemoprevention is inhibition of neoplastic disease by naturally
occurring or synthetic chemical agents. Dithiolethiones inhibit production
of experimentally produced tumors by elevating the expression of several
genes that encode for known cytoprotective enzymes. In an effort to
discover additional molecular mechanisms mediating chemoprevention, cDNA
clones representing a gene that is transcriptionally activated by
dithiolethiones, hence named dithiolethione-inducible gene-1 (DIG-1), were
isolated from rat liver via differential hybridization screening. The
deduced amino acid sequence of DIG-1 was found to have 80% identity with
the human liver enzyme leukotriene B4 (LTB4) 12-hydroxydehydrogenase.
DIG-1, purified >400-fold from the liver of rats dosed with
1,2-dithiole-3- dithiolethione, possessed an NADP+-dependent activity to
convert LTB4 to 12-oxo-LTB4. Kinetic analysis of DIG-1 revealed apparent Km
and Vmax values of 28 mM and 8.1 nmol 12-oxo-LTB4 formed/min/mg purified
protein respectively. Since LTB4 is a potent chemotactic factor and
stimulator of production of reactive oxygen species from neutrophils, the
effects of DIG-1 on these LTB4-mediated processes were examined.
Pre-incubation of LTB4 with purified rat hepatic DIG-1 greatly diminished
LTB4- stimulated migration of neutrophils. In addition, pre-incubation of
LTB4 with purified rat hepatic DIG-1 reduced LTB4-stimulated production of
superoxide anions in neutrophils, as evidenced by decreased
lucigenin-derived chemiluminescence. These results suggest that DIG-1-
catalyzed dehydrogenation of LTB4 to 12-oxo-LTB4 inhibits the pro-
inflammatory actions of LTB4. Consequently, elevation of LTB4 catabolism
via enhanced DIG-1 activity may suppress inflammatory processes implicated
in tumorigenesis.
ARTICLES
Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Lu, L. Zhong, M. E. Lonn, R. F. Burk, K. E. Hill, and A. Holmgren Penultimate selenocysteine residue replaced by cysteine in thioredoxin reductase from selenium-deficient rat liver FASEB J, August 1, 2009; 23(8): 2394 - 2402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hori, J. Ishijima, T. Yokomizo, H. Ago, T. Shimizu, and M. Miyano Crystal Structure of Anti-Configuration of Indomethacin and Leukotriene B4 12-Hydroxydehydrogenase/15-Oxo-Prostaglandin 13-Reductase Complex Reveals the Structural Basis of Broad Spectrum Indomethacin Efficacy J. Biochem., September 1, 2006; 140(3): 457 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Piton, E. Le Ferrec, S. Langouet, C. Rauch, E. Petit, F. Le Goff, A. Guillouzo, and F. Morel Oltipraz regulates different categories of genes relevant to chemoprevention in human hepatocytes Carcinogenesis, February 1, 2005; 26(2): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hori, T. Yokomizo, H. Ago, M. Sugahara, G. Ueno, M. Yamamoto, T. Kumasaka, T. Shimizu, and M. Miyano Structural Basis of Leukotriene B4 12-Hydroxydehydrogenase/15-Oxo-prostaglandin 13-Reductase Catalytic Mechanism and a Possible Src Homology 3 Domain Binding Loop J. Biol. Chem., May 21, 2004; 279(21): 22615 - 22623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Thimmulappa, K. H. Mai, S. Srisuma, T. W. Kensler, M. Yamamoto, and S. Biswal Identification of Nrf2-regulated Genes Induced by the Chemopreventive Agent Sulforaphane by Oligonucleotide Microarray Cancer Res., September 15, 2002; 62(18): 5196 - 5203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Talalay and J. W. Fahey Phytochemicals from Cruciferous Plants Protect against Cancer by Modulating Carcinogen Metabolism J. Nutr., November 1, 2001; 131(11): 3027S - 3033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Kelly, E. M. Ellis, M. M. Manson, S. A. Chanas, G. J. Moffat, R. McLeod, D. J. Judah, G. E. Neal, and J. D. Hayes Chemoprevention of Aflatoxin B1 Hepatocarcinogenesis by Coumarin, a Natural Benzopyrone That Is a Potent Inducer of Aflatoxin B1-Aldehyde Reductase, the Glutathione S-Transferase A5 and P1 Subunits, and NAD(P)H:Quinone Oxidoreductase in Rat Liver Cancer Res., February 1, 2000; 60(4): 957 - 969. [Abstract] [Full Text]
|
|
|
|
 |
|
 J.-S. Wang, X. Shen, X. He, Y.-R. Zhu, B.-C. Zhang, J.-B. Wang, G.-S. Qian, S.-Y. Kuang, A. Zarba, P. A. Egner, et al. Protective Alterations in Phase 1 and 2 Metabolism of Aflatoxin B1 by Oltipraz in Residents of Qidong, People's Republic of China J Natl Cancer Inst, February 17, 1999; 91(4): 347 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. B. Clish, B. D. Levy, N. Chiang, H.-H. Tai, and C. N. Serhan Oxidoreductases in Lipoxin A4 Metabolic Inactivation. A NOVEL ROLE FOR 15-OXOPROSTAGLANDIN 13-REDUCTASE/LEUKOTRIENE B4 12-HYDROXYDEHYDROGENASE IN INFLAMMATION J. Biol. Chem., August 11, 2000; 275(33): 25372 - 25380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Dick, M.-K. Kwak, T. R. Sutter, and T. W. Kensler Antioxidative Function and Substrate Specificity of NAD(P)H- dependent Alkenal/one Oxidoreductase. A NEW ROLE FOR LEUKOTRIENE B4 12-HYDROXYDEHYDROGENASE/15-OXOPROSTAGLANDIN 13-REDUCTASE J. Biol. Chem., October 26, 2001; 276(44): 40803 - 40810. [Abstract] [Full Text] [PDF]
|
|