Hypertensive disease of pregnancy (HDP) has been associated with elevated lifetime cardiovascular risk, including stroke, myocardial disease, coronary artery disease, and peripheral arterial disease. These two entities share common risk factors such as obesity, insulin resistance, diabetes, and hypertension. This article will evaluate the current literature on the maternal and fetal cardiovascular risks posed by HDP. The landmark study by Barker et al. demonstrated increased cardiovascular risk in growth-restricted infants, which may also be associated with HDP. Research has demonstrated the effects that HDP may have on the vascular and nephron development in offspring, particularly with respect to endothelial and inflammatory markers. In order to control for confounding variables and better understand the relationship between HDP and lifetime cardiovascular risk, future research will require following blood pressure and metabolic profiles of the parturients and their offspring.
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.
In the intestines, the nuclear receptors Fxr and Pxr regulate the transcription of metabolizing enzymes and transporters that dictate the absorption of nutrients and xenobiotics.Here, we sought to determine whether Fxr and Pxr signaling pathways are disrupted in response to high circulating concentrations of steroid hormones late in pregnancy leading to altered transporter expression. To test this, ileum were collected from virgin and pregnant C57BL/6 mice on gestation days 14, 17 and 19.Ileum from pregnant mice exhibited suppression of Fgf15 and Cyp3a11 mRNAs, which are the prototypical target genes for Fxr and Pxr, respectively. An overall reduction in the expression of apical efflux transporters, including Mdr1, Mrp2 and Bcrp, was observed in pregnant mice. To assess the ability of steroid hormones to alter intestinal nuclear receptor signaling, transporter mRNA expression was quantified in intestinal LS174T adenocarcinoma cells. In vitro data demonstrated that progestins reduced CYP3A4, MDR1 and MRP2 mRNA expression by 30 to 40%.These data suggest that progesterone may act as a mediator to negatively regulate efflux transporter expression in the mouse ileum during pregnancy possibly by reducing Pxr/PXR signaling. This may affect drug absorption and disposition during pregnancy.
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