NQ01 IN PROTECTION AGAINST BENZENE TOXICITY

描述：(改编自调查人员摘要)NAD(P)H：对苯二酚 氧化还原酶(NQO1)对苯诱导的氧化还原具有保护作用 具有造血毒性。拟议的机制是为了防止 在骨髓中形成的活性苯衍生的苯醌和氧自由基。 这种机制的主要问题是NQO1水平是不可检测的 在人类骨髓抽吸物中。这一观察结果与一个 NQO1在人骨髓中的保护作用及其增加 携带纯合子的个体观察到苯致血液毒性 NQO1突变，导致NQO1活性缺失。这个 调查人员将测试该提案中的以下两个假设 可以为NQO1的保护作用提供充分的解释 对抗苯中毒。假设1.基质微环境存在 在人骨髓中具有显著NQO1活性的原位表达 不是通过骨髓抽吸法取出的。他们提出，个人 携带纯合NQO1突变不会导致间质NQO1导致 NQO1的解毒作用受损。假设2.潜在的机制 NQO1对苯所致血液毒性的保护作用是 苯代谢物可在骨髓中诱导NQO1。在个人中 然而，携带纯合子NQO1突变，不会诱导NQO1活性 在接触苯代谢物后，导致解毒和 化学保护。这一假设将通过归纳法的特征来检验 人造血细胞系KG-1a苯代谢物对NQO1的影响 在人骨髓和潜在的靶细胞，如基质和CD34+ 祖细胞。黄曲霉毒素诱导NQO_1的分子机制 将对苯代谢物进行检查，调查人员将证实 NQO1对小鼠体内苯代谢产物毒性的影响 人的骨髓。这些实验将提供一个机械论的解释 NQO1对苯诱导的造血保护作用的研究 毒性。

DESCRIPTION: (Adapted from the Investigator's Abstract) NAD(P)H:quinone oxidoreductase (NQO1) is known to protect against benzene-induced hematopoietic toxicity. The proposed mechanism is protection against reactive benzene-derived quinones and oxygen radicals formed in bone marrow. The major problem with this mechanism is that NQO1 levels are non-detectable in human bone marrow aspirates. This observation is inconsistent with a proposed protective role for NQO1 in human bone marrow and the increased benzene-induced hematotoxicity observed in individuals carrying a homozygous NQO1 mutation which results in the absence of NQO1 activity. The investigator will test the following two hypotheses in this proposal which could provide an adequate explanation for the protective effects of NQO1 against benzene toxicity. Hypothesis 1. Stromal microenvironments exist in-situ in human bone marrow which have significant NQO1 activity and are not removed by bone marrow aspiration. They propose that individuals carrying the homozygous NQO1 mutation would not have stromal NQO1 leading to impaired detoxification by NQO1. Hypothesis 2. The mechanism underlying the protective effect of NQO1 against benzene-induced hematotoxicity is that NQO1 can be induced in bone marrow by benzene metabolites. In individuals carrying the homozygous NQO1 mutation, however, NQO1 activity is not induced after exposure to benzene metabolites leading to impaired detoxification and chemoprotection. This hypothesis will be tested by characterizing induction of NQO1 by benzene metabolites in the human hematopoietic cell line KG-1a, in human bone marrow and potential target cells such as stroma and CD34+ progenitor cells. The molecular mechanism underlying induction of NQO1 by benzene metabolites will be examined and the investigators will confirm that the toxicity of benzene metabolites is ameliorated by NQO1 induction in human bone marrow. These experiments will provide a mechanistic explanation for the protective effects of NQO1 against benzene-induced hematopoietic toxicity.