P-BENZOQUINONE, A REACTIVE METABOLITE OF BENZENE, PREVENTS THE PROCESSING OF PRE-INTERLEUKINS-1-ALPHA AND PRE-INTERLEUKINS-1-BETA TO ACTIVECYTOKINES BY INHIBITION OF THE PROCESSING ENZYMES, CALPAIN, AND INTERLEUKIN-1-BETA CONVERTING-ENZYME

Chronic exposure of humans to benzene affects hematopoietic stem and p rogenitor cells and leads to aplastic anemia. The stromal macrophage, a target of benzene toxicity, secretes interleukin-1 (IL-1), which ind uces the stromal fibroblast to synthesize hematopoietic colony-stimula ting factors. In a mouse model, benzene causes an acute marrow hypocel lularity 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-t reated mice were capable of the transcription of the IL-1 alpha gene a nd the translation of the message but showed an inability to process t he 34-kDa pre-IL-1 alpha precursor to the 17-kDa biologically active c ytokine. Treatment of normal murine stromal macrophages in culture wit h 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 su lfhydryl (SH) groups of proteins and was shown to completely inhibit t he activity of calpain, the SH-dependent protease that cleaves pre-IL- 1 alpha. In a similar manner, HQ, via peroxidase oxidation to p-benzoq uinone, 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 c ompletely inhibit the ability of the SH-dependent IL-1 beta converting enzyme. Thus benzene-induced bone marrow hypocellularity may result f rom 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 p re-IL-1 processing.