The plasma membrane glycoprotein 170 (P-gp) responsible for multidrug resistance, MDR, also may function as an efflux pump for chemical carcinogens and can be regulated by diet and nutrients. P-gp is found predominantly in the cells lining the luminal space of a variety of normal tissues, including the placenta and the endometrium of the gravid uterus. 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 and kidneys at 0, 6, 9, 12, 15 and 18 days of gestation are being processed for P-gp expression at the mRNA and protein levels. In addition, a SV40-temperature sensitive A (tsA) rat placental cell line is used to examine the effects of nutrients and diet factors in P-gp regulation. A doxorubicin-resistant rat placental cell line has been established as a model for examining P-gp function in the defense against carcinogens. We will study the regulation of P-gp by nutrients and carcinogens in wild-type and drug-resistant placental cells at the protein and mRNA levels. In addition, we are 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, known to enhance P-gp expression, and the flavonoid, kaempferol, are being investigated in the human endometrial and cervical cell lines. Special attention is paid to the two forms of MDR genes (mdr 1 and mdr 3) and their differential regulation by dietary factors and carcinogens in order to understand the physiologic regulation of P-gp.
