RGD Reference Report - Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention. - Rat Genome Database

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Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention.

Authors: Primiano, T  Li, Y  Kensler, T W  Trush, M A  Sutter, T R 
Citation: Primiano T, etal., Carcinogenesis. 1998 Jun;19(6):999-1005. doi: 10.1093/carcin/19.6.999.
RGD ID: 401959219
Pubmed: PMID:9667737   (View Abstract at PubMed)
DOI: DOI:10.1093/carcin/19.6.999   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ptgr1Ratleukotriene B4 metabolic process  IDA  RGD 
Ptgr1Ratnegative regulation of positive chemotaxis  IDA  RGD 
Ptgr1Ratnegative regulation of reactive oxygen species biosynthetic process  IDA  RGD 

Cellular Component

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ptgr1Ratcytosol  IDA cell fractionation MMO:0000679RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptgr1  (prostaglandin reductase 1)

Additional Information