Bone marrow cytotoxicity of benzo[a]pyrene is dependent on CYP1B1 but is diminished by Ah receptor-mediated induction of CYP1A1 in liver
Bone marrow cytotoxicity of benzo[a]pyrene is dependent on CYP1B1 but is diminished by Ah receptor-mediated induction of CYP1A1 in liver
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DOI：
10.1016/s0041-008x(03)00338-7
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发表时间：
2003-11-15
影响因子：
3.8
通讯作者：
Jefcoate, CR
中科院分区：
文献类型：
--
作者：
Galv치n, N;Jaskula-Sztul, R;Jefcoate, CR
我们以前使用CYP 1B 1-null小鼠证明，二甲基苯并（a）蒽（DMBA）需要CYP 1B 1的骨髓（BM）毒性。苯并（a）芘（BP），一种更有效的Ah受体配体，显示出非常不同的反应，但依赖于CYP 1B 1。用DMBA处理48小时的野生型（AhR（B））小鼠表现出BM细胞结构的大量损失和骨髓结构的破坏，这在BP处理中没有观察到。在具有低亲和力AhR（AhR（d））的同类小鼠中，DMBA和BP对BM具有相同的毒性，而AhR（d）X CYP 1B 1-null小鼠完全受到保护。原位杂交表明，CYP 1B 1 mRNA在骨髓细胞中组成型表达，并根据其AhR亲和力（BP>DMBA）被多环芳烃诱导，包括AhRd小鼠的较低水平。重要的是，在BM中检测不到CYP 1A 1 mRNA的表达。在野生型小鼠中，BP治疗导致肝脏CYP 1A 1的诱导比DMBA治疗高5倍。在AhRd小鼠中均未发生诱导。因此，肝脏代谢可能会阻止BP到达BM，在那里它可以被CYP 1B 1生物活化。骨髓细胞的流式细胞仪分析表明，DMBA处理后，粒细胞和淋巴细胞减少，但BP处理后。这些数据表明，肝脏代谢与BM毒性之间存在反比关系，这是由于PAH向BM中存在的CYP 1B 1的递送受限所致，其中仅需要非常低的组成性水平。(C)2003年爱思唯尔公司All rights reserved.
We have previously used CYP1B1-null mice to demonstrate that dimethylbenz(a)anthracene (DMBA) requires CYP1B1 for bone marrow (BM) toxicity. Benzo(a)pyrene (BP), a much more potent Ah receptor ligand, shows very different responses that nevertheless depend on CYP1B1. Wild-type (AhR(b)) mice treated with DMBA for 48 h exhibit a large loss in BM cellularity and disruption of marrow structure that is not seen for BP treatment. In congenic mice with a low affinity AhR (AhR(d)), DMBA and BP are equally toxic to the BM whereas AhR(d) X CYP1B1-null mice are fully protected. In situ hybridization demonstrates that CYP1B1 mRNA is constitutively expressed in marrow cells and is induced by PAHs according to their AhR affinity (BP>DMBA), including lower levels in AhRd mice. Importantly, expression of CYP1A1 mRNA was undetectable in BM. In wild-type mice, BP treatment leads to a fivefold greater induction of hepatic CYP1A1 than that of DMBA treatment. Neither induction occurs in AhRd mice. Thus, hepatic metabolism may prevent BP from reaching the BM, where it can be bioactivated by CYP1B1. Flow cytometric analyses of BM cells showed that there were decreases in granulocytes and lymphocytes following DMBA treatment, but not after BP treatment. These data suggest that there is an inverse relationship between liver metabolism and BM toxicity resulting from limitations on the delivery of PAH to CYP1B1 present in BM, where only very low constitutive levels are needed. (C) 2003 Elsevier Inc. All rights reserved.