Induction of granulocytic differentiation in myeloblasts by hydroquinone, a metabolite of benzene, involves the leukotriene D4 receptor.
Chronic exposure of humans to benzene (BZ), a Class I carcinogen, causes acute myelogenous leukemia, possibly via its bone marrow metabolite, hydroquinone (HQ). The ability to alter cytokine-dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential. We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin (IL)-3-dependent, granulocyte colony-stimulating factor (G-CSF)-inducible 32D myeloblasts. BZ induces granulocytic differentiation by upregulating the production of leukotriene D4 (LTD4), an essential intracellular mediator of G-CSF signaling. We report here that HQ (0.5-4.0 microM), as well as LTD4 (1 nM-10 microM), causes a concentration-dependent induction of granulocytic differentiation in 32D myeloblasts. Unlike LTD4, which induces terminal granulocytic differentiation, HQ undergoes a myeloperoxidase-dependent oxidation to bioreactive p-benzoquinone (BQ), which induces differentiation predominantly to the myelocyte stage. Studies with the highly specific LTD4 receptor antagonist, MK-571, suggest that BQ induces granulocytic differentiation in myeloblasts by activating the LTD4 receptor, thus obviating the requirement for LTD4. This was confirmed by the demonstration that HQ, in the presence of LTD4, shifts the stage-specific pattern of terminal differentiation induced by LTD4 to the incomplete (myelocyte) profile induced by HQ. The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts, as well as its ability to compete with induction by LTD4, may have a bearing on the leukemogenic potential of BZ.
Hazel
B A
BA
Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Kalf
G F
GF
D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D007213:Indomethacin / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D009195:Peroxidase / Q000037:antagonists & inhibitors; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000378:metabolism*; D015398:Signal Transduction
D006873:Hydroquinones; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; D016179:Granulocyte Colony-Stimulating Factor; C059141:verlukast; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D009195:Peroxidase; D001554:Benzene; C083169:leukotriene D4 receptor; C031927:hydroquinone; D007213:Indomethacin