Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity
Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity
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DOI：
10.1093/carcin/19.1.109
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发表时间：
1998-01-01
期刊：
影响因子：
4.7
通讯作者：
Townsend, AJ
中科院分区：
文献类型：
--
作者：
Morrow, CS;Diah, S;Townsend, AJ
利用MCM乳腺癌细胞培养的模型细胞系，研究了谷胱甘肽s -转移酶p1-1 （GSTP1-1）和多药耐药蛋白（MRP）在保护细胞免受4-硝基喹啉1-氧化物（4NQO）毒性中的作用。MCF7细胞中单独增加GSTP1-1的表达导致对4NQO衍生的核酸共价加合物的形成有有限的保护作用，但对4NQO介导的细胞毒性没有保护作用。单独增加MRP的表达可提供适度的保护，而GSTP1-1与MRP的共表达可对4NQO衍生加合物形成和4NQO细胞毒性产生高水平的保护。这种对4NQO毒性（包括核酸加合物形成和细胞毒性）的协同抗性与4NQO-谷胱甘肽（QO-SG）偶联物形成的gstp1 -1依赖性增加和QO-SG外排的MRP依赖性增加有关，这些数据表明MRP是致癌物4NQO的谷胱甘肽偶联物的重要出口转运体。gstp1 -1介导的QO-SG形成增强了4NQO毒性保护，而这种mrp依赖的外排活性是实现4NQO毒性保护的必要条件。
Model cell lines developed from MCM breast carcinoma cells were used to examine the roles of glutathione S-transferase p1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4-nitroquinoline 1-oxide (4NQO) toxicities, Increased expression of GSTP1-1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO-SG) conjugate formation and a MRP-dependent increase in QO-SG efflux, These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO, Moreover, this MRP-dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.