Kamendulis Lisa M, Isenberg Jason S, Smith Jacqueline H, Pugh George, Lington Arthur W, Klaunig James E
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202-5120, USA.
J Toxicol Environ Health A. 2002 Apr 26;65(8):569-88. doi: 10.1080/152873902317349736.
Several phthalate esters, compounds used as plasticizers in a variety of commercial products, have been shown to induce hepatic tumors in rodents. In this study, the comparative effects of phthalate monoesters on inhibition of gap junctional intercellular communication and induction of peroxisomal beta-oxidation were assessed in primary cultured hepatocytes from rats, mice, hamsters, cynomolgus monkeys, and humans. A human liver cell line was also utilized. Eight monoesters examined included mono-2-ethylhexyl phthalate (MEHP), mono-n-octyl phthalate (MNOP), mono-isononyl phthalate (MINP, 3 types, -1, -2, and -3), mono-isoheptyl phthalate (MIHP), mono-isodecyl phthalate (MIDP), and mono-(heptyl, nonyl, undecyl) phthalate (M711P). Gap junctional intercellular communication was measured 4 and 24 h after treatment by lucifer yellow dye coupling. Gap junctional intercellular communication was inhibited in rat and mouse hepatocytes by all eight monoesters in a concentration-dependent manner. In most cases, gap junctional intercellular communication was significantly reduced at the lowest concentrations tested (50 pM). Inhibition of gap junctional intercellular communication in rodent cells was substantially reversed within 24 h of monoester removal. In contrast, cell-to-cell communication was not inhibited in hamster, cynomolgus, or human hepatocytes or in a human liver cell line at any concentration examined. In rat hepatocytes, peroxisomal beta-oxidation was elevated after treatment with MEHP, MINP, MIHP, and MIDP but not MNOP or M711P, and with all but MIHP in mouse hepatocytes. The eight phthalates produced no marked change on peroxisomal beta-oxidation in hepatocytes from other species. These data provide additional evidence that the toxicological effects of phthalate esters are species specific.
几种邻苯二甲酸酯，即用于多种商业产品中的增塑剂化合物，已被证明可在啮齿动物中诱发肝肿瘤。在本研究中，评估了邻苯二甲酸单酯对大鼠、小鼠、仓鼠、食蟹猴和人类原代培养肝细胞中缝隙连接细胞间通讯的抑制作用以及过氧化物酶体β氧化的诱导作用。还使用了一种人肝细胞系。所检测的八种单酯包括邻苯二甲酸单 - 2 - 乙基己酯（MEHP）、邻苯二甲酸单正辛酯（MNOP）、邻苯二甲酸单异壬酯（MINP，3种类型，-1、-2和-3）、邻苯二甲酸单异庚酯（MIHP）、邻苯二甲酸单异癸酯（MIDP）和邻苯二甲酸单（庚基、壬基、十一烷基）酯（M711P）。在处理后4小时和24小时，通过荧光素黄染料偶联测量缝隙连接细胞间通讯。所有八种单酯均以浓度依赖性方式抑制大鼠和小鼠肝细胞中的缝隙连接细胞间通讯。在大多数情况下，在测试的最低浓度（50 pM）下，缝隙连接细胞间通讯显著降低。单酯去除后24小时内，啮齿动物细胞中缝隙连接细胞间通讯的抑制作用基本逆转。相比之下，在任何检测浓度下，仓鼠、食蟹猴或人类肝细胞或人肝细胞系中的细胞间通讯均未受到抑制。在大鼠肝细胞中，用MEHP、MINP、MIHP和MIDP处理后过氧化物酶体β氧化升高，但MNOP或M711P处理后未升高，在小鼠肝细胞中除MIHP外的所有单酯处理后过氧化物酶体β氧化均升高。这八种邻苯二甲酸酯对其他物种肝细胞中的过氧化物酶体β氧化没有产生明显变化。这些数据提供了额外的证据，表明邻苯二甲酸酯的毒理学效应具有物种特异性。
