Investigations of the Posttranslational Mechanism of Arsenite-Mediated Downregulation of Human Cytochrome P4501A1 Levels: The Role of Heme Oxygenase-1
Investigations of the Posttranslational Mechanism of Arsenite-Mediated Downregulation of Human Cytochrome P4501A1 Levels: The Role of Heme Oxygenase-1
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DOI：
10.1002/jbt.20283
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发表时间：
2009-01-01
影响因子：
3.6
通讯作者：
Kaminsky, Laurence S.
中科院分区：
文献类型：
--
作者：
Bessette, Erin E.;Fasco, Michael J.;Kaminsky, Laurence S.
亚砷酸盐是一种多环芳烃(PAHs)的环境污染物，它可以降低多环芳烃(PAHs)介导的人类细胞色素P1A1(CyP1A1)的上调，这种酶可以将多环芳烃生物激活为致癌代谢产物。从机制上讲，虽然转录下调有助于这些影响，但翻译后调控的作用已被牵连，但尚未得到证实。我们假设亚砷酸盐诱导血红素加氧酶-1(HO-1)，使细胞色素P1A1或细胞内的血红素池分解，从而下调细胞色素P1A1的表达。在48h观察期内，亚砷酸盐(5mU M)可诱导HepG2细胞HO-1mRNA表达增加7.4倍，并上调HO-1蛋白表达。亚砷酸盐可使多环芳烃苯并[k]荧菲(BKF)对细胞色素P1A1的诱导作用降低50%，而靶向人HO-1基因的siRNA可将亚砷酸盐对细胞色素P1A1诱导的细胞色素P1A1的下调作用从54%降至27%。重组HO-1在体外对细胞色素P1A1血红素的降解作用不明显。总之，这些发现表明，亚砷酸盐诱导的HO-1减少细胞内的血红素库的翻译后机制可能有助于亚砷酸盐介导的细胞色素P1A1的下调。(C)2009年Wiley期刊公司J Biochem Mol Toxicol 23：222-232,2009；在线发表在Wiley InterScience(www.intercience.wiley.com)上。DOI 10：1002/jbt.20283
Arsenite, an environmental cocontaminant of polycyclic aromatic hydrocarbons (PAHs), diminishes the PAH-mediated upregulation of human CYP1A1, the enzyme that bioactivates PAHs to carcinogenic metabolites. Mechanistically, while transcriptional downregulation contributes to these effects, a role for posttranslational regulation has been implicated but not proven. We hypothesize that arsenite induces heme oxygenase-1 (HO-1), which catabolizes CYP1A1 heme or cellular heme pools, thereby downregulating CYP1A1. Arsenite (5 mu M), in HepG2 cells, induced HO-1 mRNA 7.4-fold over the 48 h observation period, and it upregulated HO-1 protein expression. Arsenite decreased the induction of CYP1A1 by a PAH, benzo[k]fluoranthene (BKF), by 50%; and transfection of HepG2 cells with siRNA targeting the human HO-1 gene, reduced the arsenite downregulation of BKF-induced CYP1A1 from 54% to 27%, relative to untransfected cells. Reconstituted HO-1 did not significantly catabolize CYP1A1 heme in vitro. Together these findings demonstrate that a posttranslational mechanism involving decreases in the cellular heme pool by arsenite-induced HO-1 may contribute to arsenite-mediated downregulation of CYP1A1. (C) 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:222-232, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10:1002/jbt.20283