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Induction of Xenobiotic Metabolizing Enzymes and Transporters in Human Intestinal Cells by Pregnancy‐Related Hormones
Author(s) -
Moscovitz Jamie E,
HerreraGarcia Guadalupe,
Guo Grace L,
Aleksunes Lauren M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.713.7
Subject(s) - pregnane x receptor , multidrug resistance associated protein 2 , hormone , endocrinology , medicine , abcg2 , efflux , transporter , calcitriol receptor , biology , atp binding cassette transporter , chemistry , biochemistry , transcription factor , vitamin d and neurology , gene , nuclear receptor
The intestine expresses many critical xenobiotic metabolizing enzymes and transporters that regulate oral absorption and fecal excretion. Important nutrients and vitamins are absorbed at this interface, and as a result expression of these enzymes and transporters are tightly regulated. While it is known that gastrointestinal motility decreases during pregnancy, additional molecular changes in intestinal cells have yet to be investigated. To determine whether pregnancy alters intestinal disposition pathways, RNA and protein were collected from human colon adenocarcinoma LS174T cells cultured in media supplemented with 20% serum from either non‐pregnant or pregnant women (weeks 31 to 39 of gestation). In intestinal cells treated with pregnant serum, the mRNA expression of the CYP3A4 enzyme, basolateral efflux transporters OSTα and MRP3, as well as the luminal efflux transporters MDR1, MRP2 and BCRP were induced 2‐ to 4‐fold as compared to cells treated with non‐pregnant serum. MRP3 protein exhibited a 2‐fold up‐regulation when treated with pregnant serum. Profiling of differentially expressed genes (induction of CYP3A4 and MDR1 along with down‐regulation of the SHP transcription factor) suggested that serum from pregnant women is activating the Pregnane X Receptor (PXR). Further mechanistic studies revealed that progesterone and its sulfated metabolite PM5S may be responsible, in part, for expression changes observed in cells treated with pregnant serum. Because MDR1, MRP2 and BCRP are important to the luminal efflux of endocrine disrupting chemicals, such as mycotoxins, perfluorinated chemicals, and pesticides, activation of intestinal PXR by hormones in pregnant serum may be an adaptive response to decrease systemic absorption and in turn, fetal exposure. Support or Funding Information F31HD082965, R01ES020522, T32ES007148, P30ES005022