Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells
Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells
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DOI：
10.1016/s0041-008x(03)00220-5
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发表时间：
2003-09-01
影响因子：
3.8
通讯作者：
Gallagher, EP
中科院分区：
文献类型：
--
作者：
Gardner, JL;Doi, AM;Gallagher, EP
4-羟基壬烯醛（4HNE）是一种高度诱变和细胞毒性的α， β -不饱和醛，可在子宫内胎盘暴露于促氧化化合物时产生。细胞对4HNE损伤的保护是由醇脱氢酶（ADH）、醛还原酶（ALRD）、醛脱氢酶（ALDH）和谷胱甘肽s -转移酶（GST）提供的。在本研究中，我们在一组成人和妊娠中期产前肝组织中比较了醛代谢酶对4HNE的解毒作用，并报告了体外对致癌性4HNE解毒的毒理学影响。与成人肝脏相比，产前肝脏亚细胞组分中4HNE氧化和还原的初始速率降低了两到五倍，并且在产前或成人细胞质组分中均未检测到4HNE的GST结合率。肝细胞质的gsh亲和纯化在两个年龄组中产生了可检测的和大致相等的GST-4HNE结合率。与产前肝脏中4HNE的低效氧化和还原代谢一致，从产前肝脏中制备的细胞质组分相对于成年人显示出对4HNE蛋白加合物形成的保护能力下降。产前肝造血干细胞（HSC），它构成了产前肝细胞群的显著百分比。对4HNE表现出ALDH活性，但通过ALRD、ADH和GST对4HNE几乎没有还原或共轭能力。暴露于5mum 4HNE的培养HSC表现出活力丧失，并容易形成一个或多个高分子量4HNE蛋白加合物。总的来说，我们的研究结果表明，与成年人相比，孕中期胎儿肝脏对4HNE的解毒能力较低，并且4HNE的低效解毒是敏感的产前肝细胞靶点对4HNE损伤的易感性增加的基础。(C) 2003 Elsevier Inc.版权所有。
4-hydroxynonenal (4HNE) is a highly mutagenic and cytotoxic alpha,beta-unsaturated aldehyde that can be produced in utero during transplacental exposure to prooxidant compounds. Cellular protection against 4HNE injury is provided by alcohol dehydrogenases (ADH), aldehyde reductases (ALRD), aldehyde dehydrogenases (ALDH), and glutathione S-transferases (GST). In the present study, we examined the comparative detoxification of 4HNE by aldehyde-metabolizing enzymes in a panel of adult and second-trimester prenatal liver tissues and report the toxicological ramifications of ontogenic 4HNE detoxification in vitro. The initial rates of 4HNE oxidation and reduction were two- to fivefold lower in prenatal liver subcellular fractions as compared to adult liver, and the rates of GST conjugation of 4HNE were not detectable in either prenatal or adult cytosolic fractions. GSH-affinity purification of hepatic cytosol yielded detectable and roughly equivalent rates of GST-4HNE conjugation for the two age groups. Consistent with the inefficient oxidative and reductive metabolism of 4HNE in prenatal liver, cytosolic fractions prepared from prenatal liver exhibited a decreased ability to protect against 4HNE-protein adduct formation relative to adults. Prenatal liver hematopoietic stem cells (HSC), which constitute a significant percentage of prenatal liver cell populations. exhibited ALDH activities toward 4HNE, but little reductive or conjugative capacity toward 4HNE through ALRD, ADH, and GST. Cultured HSC exposed to 5 muM 4HNE exhibited a loss in viability and readily formed one or more high molecular weight 4HNE-protein adduct(s). Collectively, our results indicate that second trimester prenatal liver has a lower ability to detoxify 4HNE relative to adults, and that the inefficient detoxification of 4HNE underlies an increased susceptibility to 4HNE injury in sensitive prenatal hepatic cell targets. (C) 2003 Elsevier Inc. All rights reserved.