Pregnancy Decreases Rat CYP1A2 Activity and Expression

Abstract

Pregnancy results in increased CYP3A- and CYP2D6-mediated clearance but decreases the clearance of CYP1A2 probe drugs. The aim of this study was to determine whether the decreased CYP1A2 activity during human pregnancy could be explained by decreased expression of CYP1A2 protein and mRNA using the rat as a model. Potential mechanisms leading to decreased CYP1A2 activity and expression were also investigated. Hepatic CYP1A2 activity, protein, and mRNA were measured during mid- and late gestation and compared to nonpregnant control levels. In addition, the effect of 17-β-estradiol and progesterone on CYP1A2 mRNA levels was assessed using rat hepatocytes, and the effect of estrogens or progesterone on CYP1A2 activity in vitro was tested. CYP1A2-mediated probe clearance decreased between 48 and 62% (p < 0.05) during pregnancy, with no difference in CYP1A2 activity between mid- and late pregnancy. This decrease in probe clearance was accompanied by a 33 ± 8% (midpregnancy) and 29 ± 27% (late pregnancy) decrease in CYP1A2 protein expression (p < 0.05) and a 53% decline in methoxyresorufin O-demethylation V(max) (p < 0.05). CYP1A2 mRNA was not significantly different from controls at midpregnancy and decreased by 27 ± 20% (p < 0.05) of control during late pregnancy. Estradiol and progesterone had no effect on CYP1A2 mRNA in rat hepatocytes and did not inhibit CYP1A2 activity. These data demonstrate that pregnancy decreases CYP1A2 activity and expression with a modest effect on CYP1A2 mRNA and suggest that the rat can be used as a model to study mechanisms by which pregnancy decreases CYP1A2 activity in humans.