The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus.

Abstract

A survey of the expression of the multidrugresistance gene (mdr) in mouse tissues revealed that a mdr mRNA species is expressed at extremely high levels in the gravid uterus. mdr mRNA expression levels increase dramatically during pregnancy compared to the relatively low levels of expression observed in the nongravid uterus. In situ hybridization experiments revealed that the increased expression of the mdr mRNA is specifically localized to the secretory epithelial cells of the endometrium. Immunocytochemistry studies with a mdr glycoprotein-specific antiserum demonstrate that the mdr glycoprotein is predominantly localized to the luminal surface of the secretory epithelial cells. These results indicate that the mdr gene expression in the uterus is controlled by the physiologic changes associated with pregnancy. Our data are consistent with a potential role for the mdr glycoprotein in the transport of substrate across the secretory epithelium of the gravid uterus.Resistance of malignant neoplasms to multiple chemotherapeutic agents is a major cause of treatment failure. Tumors initially sensitive to cytotoxic agents often recur and are refractory to multiple chemotherapeutic drugs (1). It has been inherently difficult to study such drug resistance in vivo. However, a number of highly resistant cell lines have been isolated in vitro by stepwise selection with single chemotherapeutic agents. These cell lines are often also resistant to multiple other structurally and functionally unrelated cytotoxic agents (2-6). Characteristic of such highly resistant cell lines is the amplification of a small group of closely related genes, termed mdr for multiple drug resistance (7-10).We and others have previously isolated from murine, hamster, and human cell lines cDNA clones complementary to members of the mdr gene family (7-14). The mdr phenotype can be conveyed by the transfection of murine (10)

Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins

“…No full-length mdr1b P-gp was detectable anymore in immunoblots of adrenal gland membranes of mdr1b (Ϫ͞Ϫ) mice. Despite the very high mdr1b expression normally found in the adrenal gland and in the pregnant uterus of wild-type mice (13,29), mdr1b (Ϫ͞Ϫ) mice displayed normal viability, fertility, and lifespan, and no obvious spontaneous physiological abnormalities were observed. We previously found that in mdr1a (Ϫ͞Ϫ) mice the expression of mdr1b was increased in liver and kidney, suggesting possible compensatory expression between these functionally related genes.…”

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

“…Only three of the acute leukaemias examined in this work (ALL 5, ALL 7, ALL 13) are in remission at present, all of which showed distinct expression of the drug transporter gene, however (Table II). Recently, a coincidence of the absence of mdrl gene expresssion determined by PCR in untreated nonlymphocytic leukaemias and the remission frequency observed for this type of leukaemia was found (Noonan et al, 1990 (Fairchild et al, 1987;Burt & Thorgeirsson, 1988), after gestation in the endometrium of mice (Arceci et al, 1988), and by differentiating agents in a colon carcinoma cell line (Mickley et al, 1989). Moreover, we showed an increase of resistance and mdrl mRNA levels within 72 h in a multidrug-resistant CCRF-CEM subline (Gekeler et al, 1988), and more recently in the parental cell line CCRF-CEM (Noller et al, 1991) after treatment of the cells with actinomycin D. In all these cases the mdrl gene was expressed prior to the treatment albeit at distinctly lower levels.…”

Differential recognition of mdr1a and mdr1b gene products in multidrug resistant mouse tumour cell lines by different monoclonal antibodies

“…However it has been reported that in intact cells, rates of degradation of these two gene products are similar . The different gene products have been detected in different amounts in different normal tissues in the mouse , very high levels of the mdrlb gene product being found in the uterus of the pregnant mouse where it may play an important role during gestation (Arceci et al, 1988;Greenberg et al, 1989). The possibility is that they may therefore be involved with the transport of quite different endogenous substances.…”