Induction of leukotriene B4 metabolism by cancer chemopreventive agents.

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.KeywordsCancer Chemopreventive AgentCytosolic PreparationHepatic CytosolSpray Mass SpectrumElectro Spray Mass SpectrometryThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.