title: p-Benzoquinone, a reactive metabolite of benzene, prevents the processing of pre-interleukins-1 alpha and -1 beta to active cytokines by inhibition of the processing enzymes, calpain, and interleukin-1 beta converting enzyme.
abstract: Chronic exposure of humans of benzene affects hematopoietic stem and progenitor cells and leads to aplastic anemia. The stromal macrophage, a target of benzene toxicity, secretes interleukin-1 (IL-1), which induces the stromal fibroblast to synthesize hematopoietic colony-stimulating factors. In a mouse model, benzene causes an acute marrow hypocellularity that can be prevented by the concomitant administration of IL-1 alpha. The ability of benzene to interfere with the production and secretion of IL-1 alpha was tested. Stromal macrophages from benzene-treated mice were capable of the transcription to the IL-1 alpha gene and the translation of the message but showed an inability to process the 34-kDa pre-IL-1 alpha precursor to the 17-kDa biologically active cytokine. Treatment of normal murine stromal macrophages in culture with hydroquinone (HQ) also showed an inhibition in processing of pre-IL-1 alpha. Hydroquinone is oxidized by a peroxidase-mediated reaction in the stromal macrophage to p-benzoquinone, which interacts with the sulfhydryl (SH) groups of proteins and was shown to completely inhibit the activity of calpain, the SH-dependent protease that cleaves pre-IL-1 alpha. In a similar manner, HQ, via peroxidase oxidation to p-benzoquinone, was capable of preventing the IL-1 beta autocrine stimulation of growth of human B1 myeloid tumor cells by preventing the processing of pre-IL-1 beta to mature cytokine. Benzoquinone was also shown to completely inhibit the ability of the SH-dependent IL-1 beta converting enzyme. Thus benzene-induced bone marrow hypocellularity may result from apoptosis of hematopoietic progenitor cells brought about by lack of essential cytokines and deficient IL-1 alpha production subsequent to the inhibition of calpain by p-benzoquinone and the prevention of pre-IL-1 processing.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107. IEA1347@tjuvm.tjuvm.edu
authors.forename: G F
authors.initials: GF
authors.lastname: Kalf
authors.forename: J F
authors.initials: JF
authors.lastname: Renz
authors.forename: R
authors.initials: R
authors.lastname: Niculescu
mesh_terms: D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000633:toxicity*; D016227:Benzoquinones / Q000378:metabolism* / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D002154:Calpain / Q000037:antagonists & inhibitors*; D020170:Caspase 1; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011498:Protein Precursors; D011994:Recombinant Proteins; C043830:interleukin 1 precursor; C004532:quinone; D002154:Calpain; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D001554:Benzene; D007213:Indomethacin