Colinas R J, Burkart P T, Lawrence D A
Wadsworth Center, New York State Department of Health, Albany, New York 12201-0509.
Toxicol Appl Pharmacol. 1994 Nov;129(1):95-102. doi: 10.1006/taap.1994.1232.
A comparative study was undertaken in order to assess the hematotoxic effects of hydroquinone (HQ), 1,4-benzoquinone (BQ), and doxorubicin (DX) on mouse and human bone marrow (BM) cells. Initial experiments indicated that the inhibitory effects of near-ambient pO2 and HQ on granulocyte/macrophage colony-stimulating factor (GM-CSF)-induced colony formation were additive. Thus, subsequent experiments were done under conditions of continuous toxicant exposure in complete medium at physiological temperature and O2 partial pressure. Viability was measured 24 hr after exposure, and at the concentrations tested, HQ was less cytotoxic than BQ. DX did not exhibit significant cytotoxicity at the concentrations used. Both HQ and BQ were slightly more cytotoxic to mouse BM cells than to human BM cells. Dose-response analyses of HQ, BQ, or DX inhibition of GM-CSF-induced proliferative and colony-forming responses indicated that murine GM progenitors were significantly less sensitive to HQ than to the majority of myeloid BM cells that proliferated in response to GM-CSF. This preferential resistance of GM progenitors to HQ was not observed when human BM cells were used. HQ was somewhat more inhibitory to human than to mouse GM-CSF responses. Inhibition of GM-CSF-induced responses by BQ correlated closely with cytotoxicity, and DX was 1000-fold more inhibitory to GM-CSF-induced proliferative and colony-forming responses than either HQ or BQ. Again, DX appeared to be slightly more inhibitory to human BM cells than to mouse BM cells. Purified human hematopoietic progenitor cells (HPCs) were also used in the dose-response analyses of HQ, BQ, or DX inhibition of GM-CSF-induced proliferative and colony-forming responses. Inhibition of GM-CSF-induced HPC responses by HQ, BQ, and DX was very similar to that obtained when BM mononuclear cells were used, suggesting that the human HPC is a target for the direct effects of HQ, BQ, and DX.
为了评估对苯二酚（HQ）、1,4-苯醌（BQ）和阿霉素（DX）对小鼠和人骨髓（BM）细胞的血液毒性作用，进行了一项比较研究。初步实验表明，接近环境的pO2和HQ对粒细胞/巨噬细胞集落刺激因子（GM-CSF）诱导的集落形成的抑制作用是相加的。因此，后续实验是在生理温度和O2分压下于完全培养基中持续接触毒物的条件下进行的。暴露24小时后测量活力，在所测试的浓度下，HQ的细胞毒性低于BQ。DX在所使用的浓度下未表现出明显的细胞毒性。HQ和BQ对小鼠BM细胞的细胞毒性均略高于对人BM细胞的细胞毒性。对HQ、BQ或DX抑制GM-CSF诱导的增殖和集落形成反应的剂量反应分析表明，小鼠GM祖细胞对HQ的敏感性明显低于对大多数响应GM-CSF而增殖的髓系BM细胞的敏感性。当使用人BM细胞时，未观察到GM祖细胞对HQ的这种优先抗性。HQ对人GM-CSF反应的抑制作用比对小鼠的略强。BQ对GM-CSF诱导反应的抑制作用与细胞毒性密切相关，DX对GM-CSF诱导的增殖和集落形成反应的抑制作用比HQ或BQ强1000倍。同样，DX对人BM细胞的抑制作用似乎比对小鼠BM细胞的略强。纯化的人造血祖细胞（HPC）也用于HQ、BQ或DX抑制GM-CSF诱导的增殖和集落形成反应的剂量反应分析。HQ、BQ和DX对GM-CSF诱导的HPC反应的抑制作用与使用BM单核细胞时获得的结果非常相似，表明人HPC是HQ、BQ和DX直接作用的靶点。
