Regulation of Drug Disposition Gene Expression in Pregnant Mice with Car Receptor Activation

Abstract

More than half of pregnant women use prescription medications in order to maintain both maternal and fetal health. The constitutive androstane receptor (Car) critically affects the disposition of chemicals by regulating the transcription of genes encoding metabolic enzymes and transporters. However, the effects of Car activation on chemical disposition during pregnancy are unclear. This study aims to determine the degree to which pregnancy alters the expression of drug metabolizing enzymes and transporters in response to the pharmacological activation of Car. To test this, pregnant C57BL/6 mice were administered IP doses of vehicle, or a potent Car agonist, TCPOBOP, on gestation days 14, 15 and 16. Hepatic mRNA and protein expression of Car target genes (phase I, II and transporters) were quantified on gestation day 17. Pregnancy-related changes, such as induction of Cyp2b10, Ugt1a1 and Sult1a1 and repression of Ugt1a6, Gsta1, Gsta2 and Mrp6, were observed. Interestingly, the induction of Cyp2b10, Gsta1, Gsta2 and Mrp2-4 mRNAs by TCPOBOP was attenuated in maternal livers suggesting that Car activation is impeded by the biochemical and/or physiological changes that occur during gestation. Taken together, these findings suggest that pregnancy and pharmacological activation of Car can differentially regulate the expression of drug metabolism and transport genes.

Association Between miR-605 A>G, miR-608 G>C, miR-631 I>D, miR-938 C>T, and miR-1302-3 C>T Polymorphisms and Risk of Recurrent Implantation Failure

“…22 Over one-half of all pregnant women use prescription medications to maintain both maternal and fetal health. 23 Therefore, in some cases, drug metabolism is associated with the maintenance of pregnancy. For example, folate supplementation is recommended for pregnant women because deficient folate intake increases the risk of spontaneous abortion.…”

“…1 Notably, a number of studies have shown that miRNAs can specifically affect infertility and the human reproductive system, 15 and it has recently been reported that miRNAs can regulate RIF occurrence. 16 In this study, we selected 5 miRNA polymorphisms that were previously identified to be indirectly related to pregnancy outcome, miR-605A>G (rs2043556), miR-608G>C (rs4919510), miR-631I>D (rs5745925), miR-938C>T (rs12416605), and miR-1302-3C>T (rs7589328), [17][18][19][20][21][22][23][24][25][26][27][28] and measured their frequencies in Korean women with RIF and control participants. These miRNAs have all been associated with pregnancy complications and/or fetal loss.…”

Sex- and Gender-Based Pharmacological Response to Drugs

“…It also depends on phase 1 and 2 drug-metabolizing enzymes and transporters that exhibit sex differences in expression and activity (Soldin and Mattison, 2009;Soldin et al, 2011;Yang et al, 2012;Franconi and Campesi, 2014a,b) (summarized in Supplemental Table 1). The expression and activity of these enzymes and multidrug resistance protein are regulated by endogenous factors, such as genetics, age, sex, sex hormones, and microbiota, as well as by exogenous factors, such as drugs, diet, and environmental pollutants, which in part act through the nuclear receptors constitutive androstane receptor, pregnane X receptor, and aryl hydrocarbon receptor (AhR) (Smirnova, 2012;Bright et al, 2016). Notably, AhR, constitutive androstane receptor, and pregnane X receptor exhibit sexually biased expression and mode of action (Hernandez et al, 2009;Lu et al, 2013).…”

The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide‐Induced Oxidative Stress through Activation of Nrf2

“…The reason may be that in addition to Nrf2, GCLC is also regulated by Nrf1 and pregnane X receptor (PXR); PXR is highly expressed in the liver and regulates the transcriptional expression of drug metabolizing enzymes [ 26 , 27 ]. Besides, MRP2 is also regulated by numerous nuclear factors such as FXR, CAR, and PXR [ 28 – 30 ]. Hence, though the induction of Nrf2 by LEE contributes to the downstream induction of GCLC and MRP2, the regulation of GCLC and MRP2 by Nrf2 is partial but important.…”