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首页> 外文期刊>Archives of Toxicology >The rodent nongenotoxic hepatocarcinogen and peroxisome proliferator nafenopin inhibits intercellular communication in rat but not guinea-pig hepatocytes, perturbing S-phase but not apoptosis.
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The rodent nongenotoxic hepatocarcinogen and peroxisome proliferator nafenopin inhibits intercellular communication in rat but not guinea-pig hepatocytes, perturbing S-phase but not apoptosis.

机译：啮齿动物非遗传毒性肝致癌物和过氧化物酶体增殖物纳非诺平抑制大鼠的细胞间通讯，但不抑制豚鼠肝细胞，干扰S期，但不干扰细胞凋亡。

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Previously, we have shown that the peroxisome proliferator (PP), nafenopin, induces S-phase in rat hepatocytes and suppresses apoptosis in hepatocytes from both rat and guinea-pig. Here, we confirm and extend these findings by defining the time course of growth perturbation and by correlating this with species differences in loss of gap junctional intercellular communication (GJIC). GJIC is associated with nongenotoxic carcinogenesis, possibly reflecting a tumour suppresser role of the connexins. Fluorescence microscopy of Hoechst 33258-stained rat or guinea-pig hepatocyte monolayers showed 1% apoptosis during the first 8 h of culture, peaking to 2-2.5% at 20-24 h. Nafenopin suppressed apoptosis compared with controls in both rat and guinea-pig, measured at 20 h and 24 h onwards, respectively. The induction of S-phase in rat hepatocytes by nafenopin could be detected as early as 4 h after compound addition whereas S-phase was not altered by nafenopin in guinea-pig hepatocytes. Intercellular communication as measured by intercellular transfer of microinjected Lucifer Yellow CH was observed during the first 14 h of primary rat hepatocyte culture peaking at a maximum value of 88 +/- 3.0% after 7 h. In hepatocyte cultures from guinea-pig, dye-coupling levels were maintained between 88 +/- 3.0 and 93 +/- 3.0% within 2-10 h of culture and by 12 h showed only a slight decrease to 72 +/- 3.0%. In the rat, significant inhibition was observed at 4 h after administration of nafenopin since GJIC was reduced by 20 +/- 5% compared with vehicle control. By contrast, in the presence of nafenopin, the level of dye-coupling between guinea-pig hepatocytes did not decrease but remained between 85 +/- 5 and 93 +/- 3.0%, similar to that observed in control guinea-pig cultures. The data obtained contribute to our understanding of the role of GJIC inhibition in the perturbation of cell survival and proliferation caused by nongenotoxic hepatocarcinogens.
机译：以前，我们已经证明过氧化物酶体增殖物（PP）萘芬普生在大鼠肝细胞中诱导S期并抑制大鼠和豚鼠肝细胞的凋亡。在这里，我们通过定义生长扰动的时间过程并将其与间隙连接细胞间通讯（GJIC）损失中的物种差异相关联，从而确认并扩展了这些发现。 GJIC与非遗传毒性致癌作用有关，可能反映了连接蛋白的抑癌作用。 Hoechst 33258染色的大鼠或豚鼠肝细胞单层的荧光显微镜显示在培养的前8小时内凋亡为1％，在20-24小时达到2-2.5％的峰值。在大鼠和豚鼠中，分别于20小时和24小时开始，萘芬平与对照组相比均能抑制凋亡。化合物添加后最早可在4 h时检测到萘酚对大鼠肝细胞S相的诱导作用，而豚鼠肝细胞中萘酚对S期的诱导作用却没有改变。通过显微注射的路西法黄CH的细胞间转移测量的细胞间通讯在原代大鼠肝细胞培养的前14小时内观察到，在7小时后达到最大值88 +/- 3.0％。在豚鼠的肝细胞培养物中，染料偶联水平在培养的2-10 h内保持在88 +/- 3.0至93 +/- 3.0％之间，到12 h则仅略微下降至72 +/- 3.0％ 。在大鼠中，纳芬普汀给药后4小时观察到明显的抑制作用，因为与媒介物对照相比，GJIC降低了20 +/- 5％。相反，在存在萘芬平的情况下，豚鼠肝细胞之间的染料偶联水平没有降低，但仍保持在85 +/- 5至93 +/- 3.0％之间，与在对照豚鼠培养物中观察到的相似。获得的数据有助于我们理解GJIC抑制在扰动非基因毒性肝癌致癌细胞存活和增殖中的作用。

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