Hepatic drug metabolism plays a key role in determining drug response and safety. Studies of drug metabolism generate valuable information about regulation of genes encoding drug-metabolizing enzymes and enzyme functions that are critical in developing dosing guideline. However, current knowledge is insufficient to support dosing guideline for pregnant women. Specifically, substrates of a major drug-metabolizing enzyme CYP2D6 show increased elimination during pregnancy, but the underlying mechanisms are completely unknown largely due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy, recapitulating the clinically reported changes in CYP2D6-mediated drug metabolism. In these mice, pregnancy had minimal effects on the expression of hepatocyte nuclear factor (HNF) 4a, the transcription factor controlling basal CYP2D6 expression. Krppel-like factor (KLF) 9 and small heterodimer partner (SHP) were found up- and down-regulated in Tg-CYP2D6 mouse livers during pregnancy, respectively. KLF9 enhanced HNF4a-mediated transactivation of the CYP2D6 promoter whereas SHP repressed it. Retinoic acid (RA), an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy. These results indicate that interplay among hepatic transcription factors HNF4a, SHP, and KLF9 underlies CYP2D6 induction during pregnancy, and that retinoic acid is a potential trigger. This is the first report on the mechanisms underlying CYP2D6 induction and illustrates the utility of humanized mice as an in vivo model to study altered drug disposition during pregnancy.
Krüppel-like factor 9 promotes hepatic cytochrome P450 2D6 expression during pregnancy in CYP2D6-humanized mice.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Sex, Specimen part, Treatment
View SamplesThese microarrays were performed for use in a genome-wide scan for LPS-regulated genes in mouse macrophages, in order to construct a list of LPS-regulated genes for detailed interrogation on custom microarrays (see GSE19490 for custom array analysis).
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Specimen part
View SamplesThese microarrays were performed for use in a genome-wide scan for LPS-regulated genes in human monocyte-derived macrophages, in order to construct a list of LPS-regulated genes for detailed interrogation on custom microarrays (see GSE19482 for custom array analysis).
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Specimen part
View SamplesIdentification of imprinted genes expressed in adult CD3+ splenocytes
Hematopoietic reconstitution with androgenetic and gynogenetic stem cells.
Sex, Age, Specimen part
View SamplesBACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability.
Knockdown of the schizophrenia susceptibility gene <i>TCF4</i> alters gene expression and proliferation of progenitor cells from the developing human neocortex.
Sex, Specimen part, Cell line
View SamplesIn euakryotes, mRNAs must be exported from the nucleus to the cytsoplasm. NXF2 is highly expressed in the mouse male germ cells. We are interested in its function in spermatogenesis, espically in the nuclear RNA export in the testis. To this end, we made Nxf2 mutant mice by gene targeting. In an attempt to identify the mRNA substrates of NXF2, we perform the microarray experiments on testes.
Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
HIV‐exposed seronegative commercial sex workers show a quiescent phenotype in the CD4+ T cell compartment and reduced expression of HIV‐dependent host factors.
No sample metadata fields
View SamplesUnderstanding why some indidivual resist HIV-1 infection despite continued exposure is an important goal for vaccine development.
HIV‐exposed seronegative commercial sex workers show a quiescent phenotype in the CD4+ T cell compartment and reduced expression of HIV‐dependent host factors.
No sample metadata fields
View SamplesTo determine the effect on gene expression of intratumoral injection of the Toll-like receptor agonist CpG1826. MC38 colon cancer cells were injected subcutaneously into C57BL/6 mice and allowed to establish until ~40 mm2.
Toll-Like Receptor Triggering and T-Cell Costimulation Induce Potent Antitumor Immunity in Mice.
Specimen part
View Samples