NUTRITIONAL REGULATION OF CARCINOGENS IN PLACENTA-RELATED CELLS

质膜糖蛋白170（P-gp）是多药耐药的主要机制之一， 耐药，MDR，也可以作为一个外排泵的化学 致癌物质，并受膳食营养素的调节。 P-gp在正常 组织，主要是在细胞内衬的管腔空间的各种 包括胎盘和妊娠妇女子宫内膜 子宫 最近，我们的实验室证明，P-gp介导了 化学致癌物苯并（a）芘和二甲基苯并蒽的流出， 我们认为，正常组织中的P-gp可能作为第一道防线， 对致癌物的防御。 为了检测P-gp在胃癌中的表达， 正常细胞，我们使用SV 40永生化的正常大鼠胎盘细胞 温度敏感A（tsA）突变体。 我们发现在33摄氏度时 （转化表型）P-gp未检出，但在39.5 ℃下 （正常分化表型）细胞表达显著量的P- 用单克隆抗体通过Western免疫沉淀法测定的gp蛋白 抗体，C219。 Progesterone有效地阻断了阿霉素在 分化的胎盘细胞，以及长春碱的积累， 提示胎盘细胞中P-gp可能受孕酮的调节。 然而，孕酮不是P-gp的底物， 在33 ℃下的累积和流出与39 ℃下的相似。 我们进一步从这些SV 40中开发了阿霉素抗性胎盘细胞， tsA大鼠胎盘细胞，发现P-gp增加2-4倍， 分化表型的阿霉素耐药胎盘细胞。 这是第一次证明正常分化的胎盘细胞 P-gp高表达。 P-gp在正常组织中的功能作用尚未确定。 然而，我们最近的研究结果表明，P-gp mRNA在发育过程中， 在人类胎盘组织中调节。 目前，一项关于 P-gp在大鼠妊娠期正常组织中的表达正在进行中。 大鼠胎盘、卵巢、子宫、肾上腺、肾脏和结肠粘膜细胞 在妊娠0、6、9、12、15和18天， 检测P-gp在mRNA和蛋白水平的表达。 此外，我们还在研究P-gp在人类中的调节， 子宫内膜腺癌细胞系和人宫颈癌细胞 线 饮食效应物，如视黄酸（已知其可增强 P-gp）和类黄酮，山奈酚（降低P-gp）正在被 在人子宫内膜和宫颈细胞系中进行研究，以确定 他们的影响。 mdr 1和mdr 3在胎盘相关细胞中的作用 线正在调查，以确定他们的表达在正常情况下， 生理条件。

The plasma membrane glycoprotein 170 (P-gp), responsible for multidrug resistance, MDR, may also function as an efflux pump for chemical carcinogens and is regulated by dietary nutrients. P-gp is found in normal tissues, predominately in the cells lining the luminal space of a variety of tissues, including the placenta and the endometrium of the gravid uterus. Recently, our laboratory demonstrated that P-gp mediates the efflux of chemical carcinogens, benzo(a)pyrene and dimethylbenzanthracene, and we proposed that P-gp in normal tissues may serve as a first line of defense against carcinogens. In order to examine the expression of P-gp in normal cells, we used normal rat placental cells immortalized with SV40 temperature-sensitive A (tsA) mutant. We found at 33 degrees C (transformed phenotype) P-gp was not detectable but at 39.5 degrees C (normal differentiated phenotype) cells expressed significant amounts of P- gp protein as measured by Western immunoprecipitation with the monoclonal antibody, C219. Progesterone effectively blocks adriamycin efflux in the differentiated placental cells, as well as vinblastine accumulation, indicating that P-gp in placental cells may be regulated by progesterone. However, progesterone is not a substrate for P-gp since progesterone accumulation and efflux at 33 degrees C is similar to that at 39 degrees C. We further developed doxorubicin-resistant placental cells from these SV40- tsA rat placental cells and found a 2-4 fold increase of P-gp in doxorubicin-resistant placental cells at the differentiated phenotype. This is the first demonstration of normal differentiated placental cells with high expression of P-gp. The functional role of P-gp in normal tissues has not been determined. However, our recent findings indicate that P-gp mRNA is developmentally regulated in human placental tissues. Currently, a developmental study in rats of P-gp expression in normal tissues during gestation is in progress. Rat placentas, ovaries, uteri, adrenals, kidneys, and colon muscosal cells at 0, 6, 9, 12, 15, and 18 days of gestation are being processed for examination of P-gp expression at the mRNA and protein levels. In addition, we are also studying the regulation of P-gp in a human endometrial adenocarcinoma cell line and a human cervical carcinoma cell line. Dietary effectors such as retinoic acid (which is known to enhance P-gp) and the flavonoid, kaempferol (which decreases P-gp) are being investigated in the human endometrial and cervical cell lines to determine their effects. The role of mdr1 and mdr3 in the placental-related cell lines is under investigation to determine their expression under normal physiological conditions.