Dataset Information

Expression and regulation of human fetal-specific CYP3A7 in mice.

ABSTRACT: CYP3A7 is the predominant cytochrome P450 (CYP) expressed in human fetal liver, accounting for 30-50% of the total CYP in fetal liver and 87-100% of total fetal hepatic CYP3A content. However, the lack of a rodent model limits the investigation of CYP3A7 regulation and function. Hence, double-transgenic mice expressing human pregnane X receptor (PXR) and CYP3A4/7 (Tg3A4/7-hPXR) were used to investigate the regulation and function of CYP3A7. Expression of CYP3A7 was monitored in mice that ranged in age from 14.5-d-old embryos to 8.5-d-old newborns; expression of CYP3A7 mRNA was increased before birth in the embryos and decreased after birth in the newborns. This is consistent with the observed developmental regulation of CYP3A7 protein levels and CYP3A7-mediated dehydroepiandrosterone 16?-hydroxylase activities. This developmental flux is also in agreement with previous studies that have investigated the expression of CYP3A7 in developing human liver. The regulation of CYP3A7 was further studied using hepatoblasts from the Tg3A4/7-hPXR mice. Glucocorticoids, including dexamethasone, cortisol, corticosterone, and cortisone all induced the expression of CYP3A7 mRNA, whereas rifampicin, an activator of PXR and an inducer of CYP3A4 in adult liver, had no effect on CYP3A7 expression. Cell-based promoter luciferase and chromatin immunoprecipitation assays further confirmed glucocorticoid receptor-mediated control of the CYP3A7 promoter. These findings indicate that CYP3A7 is developmentally regulated in mouse liver primarily by glucocorticoids through the glucocorticoid receptor. The Tg3A4/7-hPXR mouse model could therefore potentially serve as a tool for investigating CYP3A7 regulation and function.

SUBMITTER: Pang XY

PROVIDER: S-EPMC3281537 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Expression and regulation of human fetal-specific CYP3A7 in mice.

Pang Xiao-Yan XY Cheng Jie J Kim Jung-Hwan JH Matsubara Tsutomu T Krausz Kristopher W KW Gonzalez Frank J FJ

Endocrinology 20120117 3

CYP3A7 is the predominant cytochrome P450 (CYP) expressed in human fetal liver, accounting for 30-50% of the total CYP in fetal liver and 87-100% of total fetal hepatic CYP3A content. However, the lack of a rodent model limits the investigation of CYP3A7 regulation and function. Hence, double-transgenic mice expressing human pregnane X receptor (PXR) and CYP3A4/7 (Tg3A4/7-hPXR) were used to investigate the regulation and function of CYP3A7. Expression of CYP3A7 was monitored in mice that ranged ...[more]

PMID: 22253426

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Project description:Regulated expression of cell adhesion molecules could be critical in the proliferation, sequestration, and maintenance of stem/progenitor cells. Therefore, we determined fetal and adult stage-specific roles of cell adhesion in liver cell compartments.We performed immunostaining for the adhesion molecules, E-cadherin and Ep-CAM, associated proteins, beta-catenin and alpha-actinin, hepatobiliary markers, albumin, alpha-fetoprotein, and cytokeratin-19, and the proliferation marker, Ki-67. Expression of albumin was verified by in situ mRNA hybridization.In the fetal liver, hepatoblasts showed extensive proliferation with wide expression of E-cadherin, beta-catenin, and alpha-actinin, although Ep-CAM was expressed in these cells less intensely and focally in the cell membrane to indicate weak cell adhesion. Hepatoblasts in ductal plate and bile ducts showed less proliferation and Ep-CAM was intensely expressed in these cells throughout the cell membrane, indicating strong adhesion. In some ductal plate cells, beta-catenin was additionally in the cytoplasm and nucleus, suggesting active cell signaling by adhesion molecules. In adult livers, cells were no longer proliferating and E-cadherin, beta-catenin, and alpha-actinin were expressed in hepatocytes throughout, whereas Ep-CAM was expressed in only bile duct cells. Some cells in ductal structures of the adult liver with Ep-CAM coexpressed albumin and cytokeratin-19, indicating persistence of fetal-like stem/progenitor cells.Regulated expression of Ep-CAM supported proliferation in fetal hepatoblasts through weak adhesion and helped in biliary morphogenesis by promoting stronger adhesion in hepatoblasts during this process. Restriction of Ep-CAM expression to bile ducts in the adult liver presumably facilitated sequestration of stem/progenitor cells. This stage-specific and cell compartment-related regulation of adhesion molecules should be relevant for defining how liver stem/progenitor cells enter, exit, and remain in hepatic niches during both health and disease.

Project description:Inflammation is central to the mechanisms of parturition, but the lack of understanding of how it is controlled in normal parturition hampers our ability to understand how it may diverge resulting in preterm birth. Cell-free fetal DNA is found in the amniotic fluid, and it is thought to be able to activate inflammation as a danger-associated molecular pattern. Although its levels increases with gestational age, its effect has not been studied on the human fetal membranes. Thus, the aim of this study was to determine if the fetal DNA can trigger inflammation in the human fetal membranes and, thus, potentially contribute to the inflammatory load. Isolated human amniotic epithelial cells and fetal membrane explants were treated apically with fetal DNA causing the translocation of NF-KB into the nucleus of cells and throughout the cells of the explant layers with time. Fetal membrane explants were treated apically with either small or larger fragments of fetal DNA. IL-6, TNFα, and GM-CSF secretion was measured by ELISA, and pro-MMP2 and pro-MMP9 activity was measured by zymography from apical and basal media. Increased apical IL-6 secretion and basal pro-MMP2 activity was seen with small fragments of fetal DNA. When the data were disaggregated based on fetal sex, males had significant increases in IL-6 secretion and basal increased activity in pro-MMP2 and 9, whereas females had significantly increased basal secretion of TNFα. This was caused by the smaller fragments of fetal DNA, whereas the larger fragments did not cause any significant increases. Male fetal DNA had significantly lower percentages of methylation than females. Thus, when the cytokine and pro-MMP activity data were correlated with methylation percentage, IL-6 secretion significantly correlated negatively, whereas GM-CSF secretion positively correlated. These data support the role of fetal DNA as an inflammatory stimulus in the FM, as measured by increased NF-κB translocation, cytokine secretion, and increased pro-MMP activity. However, the data also suggested that the responses are different from FM tissues of male and female fetuses, and both the fragment size and methylation status of the fetal DNA can influence the magnitude and type of molecule secreted.

Dataset Information

Expression and regulation of human fetal-specific CYP3A7 in mice.

Publications

Expression and regulation of human fetal-specific CYP3A7 in mice.

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