Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells
Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells
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DOI：
10.1016/j.freeradbiomed.2008.01.024
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发表时间：
2008-04-15
影响因子：
7.4
通讯作者：
Kumagai, Yoshito
中科院分区：
文献类型：
--
作者：
Taguchi, Keiko;Shimada, Megumi;Kumagai, Yoshito
9，10-菲醌（PQ）是空气中颗粒物的一种成分，通过两电子还原为9，10-二羟基菲（PQH（2）），引起显着的细胞蛋白质氧化和细胞毒性，这与活性氧的传播有关（K. Taguchi等人，Free Radic. 43：789-799，2007）。在本研究中，我们探索了PQ解毒的生物转化途径。将人肺上皮A549细胞暴露于PQ，导致培养基中出现一种未知代谢产物，该代谢产物被鉴定为PQH 2（PQHG）的单葡糖苷酸。尽管尿苷5 '-二磷酸葡萄糖醛酸转移酶（UGT）的多种同工酶负责PQHG的形成，但UGT 1A 10和UGT 1A 6是葡萄糖醛酸苷缀合的特别有效的催化剂。在无细胞系统中，PQ表现出快速的硫醇氧化和随后的氧消耗在二硫苏糖醇的存在下，而PQHG没有。与母体化合物不同，PQHG完全失去了氧化细胞蛋白质并导致A549细胞死亡的能力。此外，转录因子Nrf 2的缺失减少了PQHG的形成，并增加了PQ介导的小鼠原代肝细胞毒性。因此，我们得出结论，PQHG是PQ的代谢产物，通过PQH 2产生，终止其氧化还原循环并将其转运到细胞外空间。(c)2008年爱思唯尔公司All rights reserved.
9, 10-Phenanthraquinone (PQ), a component of airborne particulate matter, causes marked cellular protein oxidation and cytotoxicity through a two-electron reduction to 9,10-dihydroxyphenanthrene (PQH(2)), which is associated with the propagation of reactive oxygen species (K. Taguchi et al., Free Radic. Biol. Med. 43:789-799, 2007). In the present study, we explored a biotransformation pathway for the detoxification of PQ Exposure of human pulmonary epithelial A549 cells to PQ resulted in a time-dependent appearance of an unknown metabolite in the medium that was identified as the monoglucuronide of PQH2 (PQHG). Whereas a variety of isozymes of uridine 5'-diphosphate glucuronosyltransferase (UGTs) are responsible for PQHG formation, UGT1A10 and UGT1A6 were particularly effective catalysts for glucuronide conj Ligation. In cell-free systems, PQ exhibited a rapid thiol oxidation and subsequent oxygen consumption in the presence of dithiothreitol, whereas PQHG did not. Unlike the parent compound, PQHG completely lost the ability to oxidize cellular proteins and cause cell death in A549 cells. In addition, deletion of the transcription factor Nrf2 decreased PQHG formation and increased PQ-mediated toxicity of mouse primary hepatocytes. Thus, we conclude that PQHG is a metabolite of PQ, generated through PQH2, that terminates its redox cycling and transports it to extracellular space. (c) 2008 Elsevier Inc. All rights reserved.