THE EFFECTS OF BENZENE AND HYDROQUINONE ON MYELOID DIFFERENTIATION OFHL-60 PROMYELOCYTIC LEUKEMIA-CELLS

Chronic exposure of humans to benzene (BZ) affects hematopoietic proge nitor cells in intermediate stages of differentiation which can lead t o aplastic anemia and/or acute myelogenous leukemia and some of its va riant forms. We studied the effects of BZ and hydroquinone (HQ), a tox ic bone marrow metabolite, on the human HL-60 promyelocytic leukemic c ell line. Because the HL-60 cell is bipotential and can be induced to differentiate to monocytes or granulocytes it has been used in many st udies as a surrogate for the granulocyte/macrophage committed cell, GM -CFU. Treatment of HL-60 cells with BZ specifically induced differenti ation along the granulocytic lineage as measured by morphology, induct ion of superoxide production and chloroacetate esterase activity and t he appearance of the L12-2 surface antigen. Differentiation was induce d via the activation of protein kinase C and the phosphorylation of se veral proteins known to be involved in HL-60 cell differentiation. Sub sequent to kinase C activation, arachidonic acid was released from mem brane phospholipids and the 5-lipoxygenase pathway was activated for t he production of leukotriene D-4 (LTD(4)) required for granulocytic di fferentiation. BZ induction of granulopoiesis was prevented by preincu bation of HL-60 cells with inhibitors of protein kinase C, 5-lipoxygen ase, gamma-glutamyl transpeptidase required for the conversion of LTC( 4) to LTD(4), or LTD(4) receptor antagonists. Treatment of HL-60 cells with tetraphorbol myristate acetate (TPA), 1 alpha, 25-dihydroxyvitam in D-3 (1,25-(OH2)D-3) or interleukin-1 (IL-1) induced HL-60 cells to differentiate to monocytes/macrophages. Hydroquinone prevented inducti on to monocytes/macrophages induced by TPA or 1 alpha, 25-dihydroxyvit amin D-3, but not by IL-1 and significantly, had no effect on the indu ction of granulocytic differentiation by BZ or any other inducer. A me chanism for the induction of granulocytic differentiation by BZ is pro posed.