NUTRITIONAL REGULATION OF CARCINOGENS IN PLACENTA-RELATED CELLS

与多药相关的质膜糖蛋白170(P-gp) 抗性，MDR，也可以作为化学物质的外排泵。 致癌物质，并受饮食营养素的调节。P-gp在正常人群中被发现 组织，主要在管腔间隙内的细胞中 包括孕妇的胎盘和子宫内膜的组织 子宫。最近，我们的实验室证明了P-gp介导了 化学致癌物苯并(A)芘和二甲基苯并茂的外流， 我们认为，正常组织中的P-gp可能作为 防御致癌物质。目的：检测P-gp在卵巢癌组织中的表达。 正常细胞，我们用SV40永生化的正常大鼠胎盘细胞 温度敏感A(TSA)突变体。我们在33摄氏度发现 (转化表型)在39.5℃时检测不到P-gp (正常分化表型)细胞表达大量P- 用单抗免疫沉淀法测定GP蛋白 抗体，C219。黄体酮能有效阻断阿霉素外流。 分化的胎盘细胞，以及长春花碱的积累， 提示胎盘细胞中的P-gp可能受孕酮的调节。 然而，孕酮不是P-gp的底物，因为孕酮 33摄氏度的积聚和外排与39摄氏度的相似。 我们进一步从这些SV40细胞中培养出耐阿霉素的胎盘细胞。 TSA大鼠胎盘细胞中P-gp表达增加2-4倍 多柔比星耐药的胎盘细胞处于分化表型。 这是第一次显示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，我们最近的发现表明，P-gp mRNA是发育中的 在人类胎盘组织中受到调控。目前，一项发展研究在 大鼠孕期正常组织中P-gp的表达正在进行中。 大鼠胎盘、卵巢、子宫、肾上腺、肾脏和结肠肌肉细胞 在怀孕0、6、9、12、15和18天时正在处理 检测P-gp在mRNA和蛋白水平的表达。 此外，我们还在研究P-gp在人类体内的调节 子宫内膜腺癌细胞系和人宫颈癌细胞 排队。饮食效应物，如维甲酸(众所周知，它可以增强 P-gp)和黄酮类，山奈酚(降低P-gp) 在人类子宫内膜和宫颈细胞系中进行研究以确定 他们的影响。Mdr1和mdr3在胎盘相关细胞中的作用 LINES正在调查中，以确定它们在正常情况下的表达 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.