HORMONAL REGULATION OF MULTIDRUG RESISTANCE IN PLACENTAL TISSUES AND CELLS

多药耐药（MDR）基因编码质膜 糖蛋白170 KDa（P-gp），其作为外排泵， MDR肿瘤细胞中的化疗药物。 P-gp也表达于 从未暴露于抗癌药物的正常组织，主要在 细胞内衬各种组织的腔空间，包括 胎盘和妊娠子宫的子宫内膜 虽然 P-gp的生理重要性尚未确定，几种功能性 角色已经提出。 我们假设正常组织中的P-gp 可以作为抵抗内源性异生物质的第一道防线， 正常细胞，特别是在怀孕期间， 保护发育中的胎儿 检查大鼠胎盘和其他母体组织的发育 妊娠期MDR的调节。 多药耐药基因1在大鼠卵巢中的表达 最初很高，在妊娠第6天后下降。 胎盘和 子宫在妊娠15周时具有最高的mdr 1表达， 随后是18周的妊娠，这与以前的报告相似 并反映了孕鼠体内的孕酮分布。 结肠黏膜 在18周时有高水平的mdr 1表达， 在整个妊娠期间，观察到肾脏和肾上腺的差异。 mdr 1的表达在早期不同组织间存在差异， 妊娠中期和晚期，强烈表明mdr 1可能受到调节， 孕鼠体内的孕激素 大鼠SV 40-温度敏感（ts）A-突变体转化的胎盘 细胞系A950被用作进一步研究的模型。 大鼠 滋养层细胞系表达mdr 1b的水平明显高于 正常分化表型（A950 H，非允许温度） 比在A950 L细胞中更高（容许温度，恶性表型）。 在A950 L和A950 H中观察到mdr 2的相似表达。 的 MDR在第15天大鼠胎盘中的高表达与 循环孕酮水平 为了确定孕酮是否在 在MDR的调节中的作用，两种类型的A950细胞均被处理 用两种浓度（5和12.5 μ M）的孕酮。 5 μ M的孕酮显著增加MDR的表达 在A950 H细胞中，而在12.5 μ M时，孕酮抑制了 MDR的表达。 两种浓度的孕酮均无影响 对A950 L细胞MDR表达的影响。 我们还检查了 脱氢异雄酮（DHEA），是孕酮的代谢产物 胎盘中的新陈代谢。 DHEA中度增强P-gp 在A950 H细胞中的产生和表达， A950 L细胞。 我们证明，MDR增强， 分化的胎盘细胞（A950 H），当暴露于妊娠 激素孕酮和脱氢表雄酮

The multidrug resistance (MDR) gene encodes a plasma membrane glycoprotein 170 KDa (P-gp), which functions as an efflux pump for chemotherapeutic drugs in MDR tumor cells. P-gp is also expressed in normal tissues never exposed to anticancer drugs, predominately in the cells lining the luminal space of a variety of tissues, including the placenta and the endometrium of the gravid uterus. Although the physiological importance of P-gp has not been defined, several functional roles have been proposed. We hypothesized that P-gp in normal tissues may serve as a first line of defense against endogenous xenobiotics in normal cells, regulated by steroids particularly during pregnancy, to protect the developing fetus. Rat placenta and other maternal tissues were examined for developmental regulation of MDR during gestation. The rat ovary expression of mdr1 was initially high and declined after day 6 of gestation. The placenta and uterus had the highest expression of mdr1 at 15 weeks of gestation, followed by 18 weeks of gestation, which is similar to previous reports and mirrors the progesterone profile in the gestating rat. Colon mucosa had a high level of mdr1 expression at 18 weeks, while no detectable differences were observed in the kidney and adrenal throughout gestation. The expression of mdr1 was different from tissue to tissue during early, mid, and late gestation, strongly suggesting that mdr1 may be regulated by gestational hormones in the pregnant rat. The rat SV40-temperature sensitive (ts) A-mutant transformed placental cell line, A950, was used a model for further investigation. The rat trophoblast cell line expressed mdr1b at significantly higher levels in the normal differentiated phenotype (A950 H, nonpermissive temperature) than in A950 L cells (permissive temperature, malignant phenotype). Similar expression of mdr2 in A950 L and A950 H was observed. The high expression of MDR in rat placenta on day 15 coincides with the circulating progesterone levels. To determine if progesterone played a role in the regulation of MDR, both types of A950 cells were treated with two concentrations (5 and 12.5 mu M) of progesterone. Progesterone at 5 mu M significantly increased the expression of MDR in A950 H cells, whereas at 12.5 mu M, progesterone inhibited the expression of MDR. Progesterone at both concentrations had no effect on MDR expression in A950 L cells. Also, we examined dehydroisoandrosterone (DHEA), which is a metabolite of progesterone metabolism in the placenta. DHEA moderately enhanced P-gp production and expression in A950 H cells with no detectable changes in A950 L cells. We demonstrated that MDR was enhanced in differentiated placental cells (A950 H) when exposed to the gestational hormones, progesterone and DHEA.