The role of the Ah receptor and p38 in Benzo[a]pyrene-7,8-dihydrodiol and Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis
The role of the Ah receptor and p38 in Benzo[a]pyrene-7,8-dihydrodiol and Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis
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DOI：
10.1074/jbc.m300780200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Tukey, RH
中科院分区：
文献类型：
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作者：
Chen, SJ;Nguyen, N;Tukey, RH
多环芳烃(PAHs)是环境中普遍存在的污染物。苯并[a]芘(B[a]P)是这类化合物的典型成员，它影响细胞信号转导通路并诱导细胞凋亡。本研究发现B[a]P代谢的最接近的致癌物反式-7，8-二羟基-7，8-二氢苯并[a]芘(B[a]P-7，8-二氢二醇-7，t-8-二氢二醇-t-9，10-环氧化物(+/-)(BPDE-2)可诱导人肝癌细胞株HepG2细胞发生凋亡。由B[a]P-7，8-二氢二醇引发的细胞凋亡与ah受体的激活和细胞色素P1A1的诱导有关，这一事件可导致BPDE-2的形成。在B[a]P-7，8-二氢二醇和BPDE-2处理下，Bcl2蛋白家族中抗和促凋亡事件的变化与线粒体细胞色素c的释放和caspase的激活有关。通过caspase激活来监测细胞凋亡的开始与丝裂原激活蛋白(MAP)激酶有关。利用小鼠Hepa1c1c7细胞和Arnt缺陷的BPRc1细胞，B[a]P-7，8-二氢二醇对MAP激酶p38的激活依赖于ah受体，表明需要通过CYP1A1进行代谢激活。这与BPDE-2激活p38形成鲜明对比，BPDE-2是一种独立于ah受体功能的事件。通过化学抑制剂p38和ERK1/2抑制多聚ADP-核糖聚合酶1(PARP-1)的caspase活性，证实MAP激酶在BPDE-2诱导的细胞凋亡中起关键作用。此外，通过Annexin V分析、细胞色素c释放和PARP-1的裂解，表明小鼠胚胎p38(-/-)成纤维细胞对BPDE-2诱导的细胞凋亡具有抵抗作用。这些结果证实了ah受体在B[a]P-7，8-二氢二醇诱导的细胞凋亡中起关键作用，而p38 MAP激酶则将亲电代谢产物如BPDE-2的作用与细胞程序性死亡的调节联系起来。
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in the environment. Benzo[ a] pyrene ( B[ a] P), a prototypical member of this class of chemicals, affects cellular signal transduction pathways and induces apoptosis. In this study, the proximate carcinogen of B[ a] P metabolism, trans-7,8-dihydroxy-7,8-dihydrobenzo[ a] pyrene ( B[ a] P-7,8-dihydrodiol) and the ultimate carcinogen, B[ a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide(+/-) ( BPDE-2) were found to induce apoptosis in human HepG2 cells. Apoptosis initiated by B[ a] P-7,8-dihydrodiol was linked to activation of the Ah receptor and induction of CYP1A1, an event that can lead to the formation of BPDE-2. With both B[ a] P-7,8-dihydrodiol and BPDE-2 treatment, changes in anti- and pro-apoptotic events in the Bcl-2 family of proteins correlated with the release of mitochondrial cytochrome c and caspase activation. The onset of apoptosis as monitored by caspase activation was linked to mitogen-activated protein ( MAP) kinases. Utilizing mouse hepa1c1c7 cells and the Arnt-deficient BPRc1 cells, activation of MAP kinase p38 by B[a]P-7,8-dihydrodiol was shown to be Ah receptor-dependent, indicating that metabolic activation by CYP1A1 was required. This was in contrast to p38 activation by BPDE-2, an event that was independent of Ah receptor function. Confirmation that MAP kinases play a critical role in BPDE-2-induced apoptosis was shown by inhibiting caspase activation of poly( ADP-ribose) polymerase 1 (PARP-1) by chemical inhibitors of p38 and ERK1/2. Furthermore, mouse embryo p38(-/-) fibroblasts were shown to be resistant to the actions of BPDE-2-induced apoptosis as determined by annexin V analysis, cytochrome c release, and cleavage of PARP-1. These results confirm that the Ah receptor plays a critical role in B[ a] P-7,8-dihydrodiol-induced apoptosis while p38 MAP kinase links the actions of an electrophilic metabolite like BPDE-2 to the regulation of programmed cell death.