Induction of granulocytic differentiation in a mouse model by benzene and hydroquinone.
Chronic exposure of humans to benzene causes acute myelogenous leukemia (AML). The studies presented here were undertaken to determine whether benzene, or its reactive metabolite, hydroquinone (HQ), affects differentiation of myeloblasts. Benzene or HQ administered to C57BL/6J mice specifically induced granulocytic differentiation of myeloblasts. The ability of these compounds to induce differentiation of the myeloblasts was tested directly using the murine interleukin 3 (IL-3)-dependent 32D.3 (G) myeloblastic cell line, and the human HL-60 promyelocytic leukemia cell line. We have previously shown that benzene treatment of HL-60 myeloblasts activates protein kinase C (PKC) and upregulates the 5-lipoxygenase (LPO) pathway for the production of leukotriene D4 (LTD4), an essential effector or granulocytic differentiation. Differentiation was prevented by sphinganine, a PKC inhibitor, and, as shown here, by LPO inhibitors and LTD4 receptor antagonists. Benzene or HQ also induces differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways normally activated by granulocyte colony stimulating factor (G-CSF) and can replace the requirement for G-CSF. While IL-3 induces a growth response in 32D.3 (G) cells, G-CSF has been shown to provide both growth and differentiated signals. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth; however, neither supports growth in the absence of IL-3. Benzene, like HQ, also provides a differentiation signal for 32D cells; however, it has no effect on their growth. Unlike G-CSF, benzene, or LTD4, each of which stimulates terminal differentiation; HQ blocks differentiation at the myelocyte stage, allowing only a small percentage of progenitors to proceed to mature segmented granulocytes. Benzene- and G-CSF-induced differentiation were prevented by the additional of either LPO inhibitors or LTD4 receptor antagonists, indicating that benzene, like G-CSF, upregulates LTD4 production. Hydroquinone-induced differentiation was not affected by the LPO inhibitors, but only by the specific receptor antagonists. Thus HQ appears to obviate the requirement for LTD4 by activating the LTD4 receptor directly.
Hazel
B A
BA
Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
O'Connor
A
A
Niculescu
R
R
Kalf
G F
GF
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism; D018077:Receptors, Leukotriene
D002273:Carcinogens; D006873:Hydroquinones; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D001094:Arachidonate 5-Lipoxygenase; D011493:Protein Kinase C; D001554:Benzene; C083169:leukotriene D4 receptor; C031927:hydroquinone