The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse

Masuyama, Hisashi; Hiramatsu, Yuji; Mizutani, Yoshihiro; Inoshita, H; Kudo, Takafumi

doi:10.1016/s0303-7207(00)00395-6

Cited by 94 publications

(74 citation statements)

References 32 publications

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“…Pregnancy-related physiological changes are likely responsible, which include 1) rising levels of pregnancy hormones, 2) potentially heightened inflammatory response, and 3) possible changes in activity and/or expression of key transcription factors involved in regulation of P450 expression. Pregnancy is accompanied by increasing plasma concentrations of female hormones (estrogens and progesterone), cortisol, and placental growth hormones (Barkley et al, 1979;Masuyama et al, 2001), which may potentially modulate hepatic P450 expression. For example, growth hormone (released in a continuous pattern) increases expression of Cyp3a41 (Sakuma et al, 2002), and estradiol and glucocorticoid can potentiate the inducing effects of growth hormones on Cyp3a41 expression (Sakuma et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Altered Cytochrome P450 Expression in Mice during Pregnancy

Koh¹,

Xie²,

Yu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnancy is known to influence hepatic drug metabolism in a cytochrome (P450)-specific manner. However, the underlying mechanisms remain unknown, in part due to a lack of experimental models to study altered drug metabolism during pregnancy. In this study, we examined how pregnancy influences expression of major P450 isoforms in mice. Liver tissues were isolated from female FVB/N-mice at different gestational time points: prepregnancy, 7, 14, and 21 days of pregnancy, and 7 days postpartum. mRNA expression levels of major P450 isoforms (Cyp1a2, Cyp2a5, Cyp2b10, Cyp2c37, Cyp2d22, Cyp2e1, Cyp3a11, and Cyp3a41) in the liver tissues were determined by quantitative real-time polymerase chain reaction. Whereas Cyp2a5 expression was unchanged, Cyp3a41 expression was significantly increased during pregnancy. In contrast, expression of Cyp1a2, Cyp2c37, Cyp2d22, Cyp2e1, and Cyp3a11 was decreased. Expression of Cyp2d22 and Cyp2e1 isoforms correlated with that of peroxisome proliferatoractivated receptor (PPAR)␣ in the mouse livers, suggesting potential involvement of PPAR␣ in down-regulation of the P450 expression during pregnancy. Effects of pregnancy on expression of other P450 mouse isoforms as well as on in vivo drug disposition remain to be characterized. These results provide a guide for future studies on P450 regulation during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Altered Cytochrome P450 Expression in Mice during Pregnancy

Koh¹,

Xie²,

Yu³

et al. 2010

Drug Metab Dispos

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“…For instance, PXR is not affected by estradiol, but shows a progesterone-mediated 50-fold induction during pregnancy. 34 On the other hand, estradiol can activate CAR by increasing nuclear translocation in a dose-dependent manner in HepG2 cells. 35 Conversely, CAR can antagonize ER-mediated transcription activation by squelching coactivator p160 in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

et al. 2004

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This study reports that Cyp3a41 gene contains 13 exons and is localized on the chromosome 5. CYP3A41 is a female-specific isoform that is predominantly expressed in the liver. Estrogen signaling is not responsible for its female specificity. CYP3A41 expression in kidney and brain is observed only in 50% of mice examined. PXR mediates dexamethasone-dependent suppression of CYP3A41. In contrast to CYP3A11, CYP3A41 expression is not induced by pregnenolone-16a-carbonitrile (PCN) in wild-type mice, but is significantly suppressed by PCN in PXR À/À mice. Phenobarbital and TCPOBOP induce CYP3A11 expression only in the presence of CAR, but have no effect on CYP3A41 expression. Immunoblot and erythromycin demethylase activity analysis reveal robust CYP3A induction after PCN treatment, which is poorly correlated to CYP3A41. These findings suggest a differential role for CAR/PXR in regulating individual CYP3A isoforms by previously characterized CYP3A inducers.

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“…PXR is activated by numerous clinically important xenobiotics, herbal products, and endogenous steroids (Chang and Waxman, 2006). Indeed, largely due to increasing hormonal levels, the hepatic expression of PXR increases by approximately 20-fold during the perinatal period in mice (Masuyama et al, 2001). PXR-mediated induction of Cyp3a and several key ABC drug efflux transporters in liver such as Mdr1, Mrp2, Mrp3, and Bcrp has been demonstrated (Guo et al, 2002;Kliewer et al, 2002;Teng et al, 2003;Anapolsky et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir

Piquette-Miller²

2010

Drug Metab Dispos

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ABSTRACT:The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was

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The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse

Cited by 94 publications

References 32 publications

Altered Cytochrome P450 Expression in Mice during Pregnancy

Altered Cytochrome P450 Expression in Mice during Pregnancy

CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

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