The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats
The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats
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DOI：
10.1016/j.tox.2007.06.102
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发表时间：
2007-10-08
期刊：
影响因子：
4.5
通讯作者：
Glauert, Howard P.
中科院分区：
文献类型：
--
作者：
Bunaciu, Rodica Petruta;Tharappel, Job C.;Glauert, Howard P.
多氯联苯（PCBs）是普遍存在的亲脂性环境污染物。部分多氯联苯同系物及同系物混合物在大鼠肝脏中具有促肿瘤活性。其活性机制尚不完全清楚，可能是多因素的。本研究的目的是研究常驻肝巨噬细胞，库普弗细胞，是否在促进多氯联苯活性中起重要作用。本研究的假设是，抑制库普弗细胞活性可以抑制多氯联苯对大鼠肝脏肿瘤的促进作用。为了验证我们的假设，我们以2,2',4,4',5,5'-六氯联苯（PCB-153，一种非二恶英样PCB）或3,3',4,4'-四氯联苯（PCB-77，一种二恶英样PCB）为启动子，研究了膳食甘氨酸（一种抑制库普弗细胞分泌活性的抑制剂）对大鼠两期肝癌模型的抑制作用。给雌性Sprague-Dawley大鼠注射二乙基亚硝胺（DEN, 150 mg/kg），然后在DEN给药后两周开始饲喂含有5%甘氨酸（或酪蛋白作为氮对照）的未精制日粮。开始给药后第3天，大鼠腹腔注射PCB-77 （300 μ mol/kg）、PCB-153 （300 μ mol/kg）或玉米油。大鼠共接受4次多氯联苯注射，每14天注射一次。最后一次注射多氯联苯后第10天处死大鼠，观察表达胎盘谷胱甘肽s -转移酶（PGST）的改变肝灶的形成情况和正常肝组织DNA合成率。甘氨酸对病灶数量和体积没有显著影响。多氯联苯-153没有显著增加肝脏的病灶体积，但增加了每个肝脏的病灶数量，但只在未饲喂甘氨酸的大鼠中出现；多氯联苯-77增加了甘氨酸喂养和对照大鼠的病灶数量和体积。甘氨酸没有改变肝脏中PCB的含量，但增加了pccb -153处理大鼠肝微粒体中7-苯氧基间苯甲酚o -脱烷基酶（BROD）的活性。甘氨酸不影响PCB-77对肝微粒体乙氧基间苯二酚o脱烷基酶活性的诱导作用。甘氨酸在pgst阳性灶中抑制肝细胞增殖，但在正常组织中无此作用。总的来说，这些结果不支持膳食甘氨酸抑制多氯联苯促进活动的假设。观察到PCB-153增加了对照大鼠每个肝脏的病灶数量，而甘氨酸喂养的大鼠则没有，然而，膳食甘氨酸减少了pgst阳性病灶的细胞增殖，这并不能让我们完全排除膳食甘氨酸的作用。但总体数据表明，Kupffer细胞可能对PCB-77和PCB-153的促瘤活性没有贡献。2007爱思唯尔爱尔兰有限公司版权所有。
Polychlorinated biphenyls (PCBs) are ubiquitious lipophilic environmental pollutants. Some of the PCB congeners and mixtures of congeners have tumor promoting activity in rat liver. The mechanism of their activity is not fully understood and is likely to be multifactorial. The aim of this study was to investigate if the resident liver macrophages, Kupffer cells, are important in the promoting activity of PCBs. The hypothesis of this study was that the inhibition of Kupffer cell activity would inhibit hepatic tumor promotion by PCBs in rats. To test our hypothesis, we studied the effects of Kupffer cell inhibition by dietary glycine (an inhibitor of Kupffer cell secretory activity) in a rat two-stage hepatocarcinogenesis model using 2,2',4,4',5,5'-hexachlorobiphenyI (PCB-153, a non-dioxin-like PCB) or 3,3',4,4'-tetrachlorobiphenyl (PCB-77, a dioxin-like PCB) as promoters. Diethylnitrosamine (DEN, 150 mg/kg) was administered to female Sprague-Dawley rats, which were then placed on an unrefined diet containing 5% glycine (or casein as nitrogen control) starting two weeks after DEN administration. On the third day after starting the diets, rats received PCB-77 (300 mu mol/kg), PCB-153 (300 mu mol/kg), or corn oil by i.p. injection. The rats received a total of 4 PCB injections, administered every 14 days. The rats were euthanized on the 10th day after the last PCB injection, and the formation of altered hepatic foci expressing placental glutathione S-transferase (PGST) and the rate of DNA synthesis in these foci and in the normal liver tissue were determined. Glycine did not significantly affect foci number or volume. PCB-153 did not significantly increase the focal volume, but increased the number of foci per liver, but only in the rats not fed glycine; PCB-77 increased both the foci number and their volume in both glycine-fed and control rats. Glycine did not alter the PCB content of the liver, but did increase the activity of 7-benzyloxyresorufin O-dealkylase (BROD) in liver microsomes from PCB-153 treated rats. However, glycine did not affect the induction of ethoxyresorufin O-dealkylase activity by PCB-77 in liver microsomes. Glycine diminished hepatocyte proliferation in PGST-positive foci, but not in normal tissue. Overall these results do not support the hypothesis that dietary glycine inhibits the promoting activities of PCBs. The observations that PCB-153 increased the number of foci per liver in control rats but not glycine-fed rats and that dietary glycine reduced cell proliferation in PGST-positive foci, however, do not allow us to completely rule out a role for dietary glycine. But the data overall indicate that Kupffer cells likely do not contribute to the tumor promoting activities of PCB-77 and PCB-153. (c) 2007 Elsevier Ireland Ltd. All rights reserved.