Altered Cytochrome P450 Expression in Mice during Pregnancy

Abstract

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.

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

“…However, when the relative abundance of the different isoforms is taken into account, the predominant hepatic Cyp enzymes (Cyp1a2, Cyp2c50, and Cyp3a11) are all considerably reduced during the course of gestation, especially at GD14. The findings with Cyp1a2 and 3a11 are in agreement with two other studies (Koh et al, 2011;Walker et al, 2011) but also extend them by demonstrating decreased expression of Cyp3a11 out to PD30. Functional data in humans indicate the human orthologs of Cyp1a2 (CYP1A2) and Cyp2c50 and 54 (CYP2C19) enzymes are also likely decreased during pregnancy, which parallels our findings (Anderson 2005).…”

“…Most of the changes in phase 1 enzymes reported in the present study are consistent with those presented elsewhere (Koh et al, 2011), as well as with the functional studies conducted in humans (Anderson, 2005). Additionally, this study provides novel information regarding the expression of Ces isoforms Pon1, Cyp2c50, and Cyp2c54 during pregnancy in mice, which has not previously been reported.…”

“…Recent studies investigated changes in rodent cytochrome P450 (Cyp) isoforms during pregnancy in mice Koh et al, 2011) and rats (He et al, 2005;Dickmann et al, 2008). However, data are lacking for some important Cyp isoforms involved in pesticide metabolism, and the regulation of hepatic Ces or Pon1 levels during pregnancy is not known.…”

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

“…Hepatic CYP3A activity in pregnant mice, for example, is increased to a similar extent as CYP3A in humans (compared with nonpregnant controls) (Mathias et al, 2006;Zhang et al, 2008;Zhou et al, 2010). In addition, hepatic Cyp1a2 mRNA is decreased during mouse pregnancy, which is consistent with CYP1A2 activity in pregnant women (Tracy et al, 2005;Koh et al, 2011).…”

Maternal Hepatic Growth Response to Pregnancy in the Mouse

“…Maternal hepatic functional adjustments include alterations in drug, lipid, cholesterol, bile acid, and glucose metabolism (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Pregnancy-induced changes in liver function tests have been reported in humans, including alterations of serum albumin and bilirubin levels, aspartate transaminase and alanine transaminase activites, and triglyceride and cholesterol concentrations in the blood (25)(26)(27)(28)(29).…”