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 Vmax (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.
Footnotes
- Received August 5, 2010.
- Accepted October 4, 2010.
↵1 Current affiliation: Amgen, Seattle, Washington.
The work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM007750]; and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant U10-HD047892].
The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035766.
ABBREVIATIONS:
- P450
- cytochrome P450
- MROD
- methoxyresorufin O-demethylation
- RLMs
- rat liver microsomes
- PCR
- polymerase chain reaction.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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