The role of polycyclic aromatic hydrocarbon metabolism in dimethylbenz[a]anthracene-induced pre-B lymphocyte apoptosis
The role of polycyclic aromatic hydrocarbon metabolism in dimethylbenz[a]anthracene-induced pre-B lymphocyte apoptosis
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DOI：
10.1006/taap.1999.8778
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发表时间：
1999-11-15
影响因子：
3.8
通讯作者：
Sherr, DH
中科院分区：
文献类型：
--
作者：
Mann, KK;Matulka, RA;Sherr, DH
先前的研究表明，两种原型PAH，苯并[a]芘（B[a]P）和7，12-二甲基苯并[a]蒽（DMBA），通过诱导骨髓前B淋巴细胞凋亡来抑制发育中的免疫系统。在骨髓基质细胞单层上生长的前B细胞组成的骨髓培养物中，前B细胞凋亡被证明是依赖于在基质细胞中表达的芳烃受体/转录因子（AhR）。然而，没有确定单独的AhR活化是否足够或者DMBA代谢是否是诱导基质细胞来源的凋亡信号所需的。为了解决这些问题，我们评估了：1）代谢不良的AhR配体诱导前B细胞凋亡的能力和2）早期DMBA代谢物诱导前B细胞凋亡的能力和机制。三种代谢不良的AhR配体，2，3，7，8-四氯二苯并-p-二恶英，3，3 '，4，4'，5-五氯联苯和3，3 '，4，4'-四氯联苯未能诱导骨髓培养物中的前B细胞凋亡，表明单独的AhR活化不足以诱导凋亡，并提示PAH代谢在诱导凋亡信号中的作用。与这一假设一致，DMBA-3，4-二氢二醇，一种早期DMBA代谢物，诱导显著的前B细胞凋亡。DMBA-3，4-二氢二醇激活AhR的能力、α-萘酮对DMBA-3，4-二氢二醇诱导的细胞凋亡的抑制以及在AhR（-）基质细胞上维持的前B细胞群中DMBA-3，4-二氢二醇诱导的细胞凋亡的显著较低水平强烈支持AhR在DMBA-3，4-二氢二醇诱导的细胞凋亡中的作用。两个DMBA代谢酶的评估，CYP 1A 1和CYP 1B 1，后者似乎是更有可能发挥作用的DMBA诱导的细胞凋亡。这些数据证实了AhR在PAM诱导的前B细胞凋亡中的作用，表明了DMBA代谢的作用，并提出了一个反馈回路，其中至少一种DMBA代谢产物增强AhR信号传导，导致诱导凋亡刺激。(C)北京：科学出版社.
Previous studies indicated that two prototypic PAH, benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA), suppress the developing immune system by inducing apoptosis in bone marrow pre-B lymphocytes. In bone marrow cultures consisting of pre-B cells growing on bone marrow stromal cell monolayers, pre-B cell apoptosis was shown to be dependent on the aryl hydrocarbon receptor/transcription factor (AhR) expressed in stromal cells. However, it was not determined if AhR activation alone is sufficient or if DMBA metabolism is required for induction of a stromal cell-derived apoptosis signal. To address these issues we assessed: 1) the ability of poorly metabolized AhR ligands to induce pre-B cell apoptosis and 2) the capacity for and the mechanism through which an early DMBA metabolite induces pre-B cell apoptosis. Three poorly metabolized AhR ligands, 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3,3',4,4',5-pentachlorobiphenyl, and 3,3',4,4'-tetrachlorobiphenyl failed to induce pre-B cell apoptosis in bone marrow cultures, indicating that AhR activation alone is not sufficient to induce apoptosis and suggesting a role for PAH metabolism in induction of an apoptosis signal. Consistent with this hypothesis, DMBA-3,4-dihydrodiol, an early DMBA metabolite, induced significant pre-B cell apoptosis. The ability of DMBA-3,4-dihydrodiol to activate the AhR, inhibition of DMBA-3,4-dihydrodiol-induced apoptosis by alpha-naphthoflavone, and the significantly lower levels of DMBA-3,4-dihydrodiol-induced apoposis in pre-B cell populations maintained on AhR(-) stromal cells strongly support a role for the AhR in DMBA-3,4-dihydrodiol-induced apoptosis. Of two DMBA-metabolizing enzymes evaluated, CYP1A1 and CYP1B1, the latter appeared to be the more likely to play a role in DMBA-induced apoptosis. These data confirm a role for the AhR in PAM-induced pre-B cell apoptosis, indicate a role for DMBA metabolism, and suggest a feedback loop in which at least one product of DMBA metabolism augments AhR signaling, leading to induction of an apoptosis stimulus. (C) 1999 Academic Press.