Document Detail


Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy.
MedLine Citation:
PMID:  23150428     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0.05) on gestational days (GD) 15 and 19 compared with the non-pregnant controls. There was no change (P > 0.05) in Cyp2d9 and Cyp2d10 mRNA. In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2.7-fold (P < 0.05) on GD19 (56.8±39.4 pmol/min/mg protein) when compared with the non-pregnant controls (20.8±11.2 pmol/min/mg protein). An increase in Cyp26a1 mRNA (10-fold) and retinoic acid receptor (Rar)β mRNA (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rarβ mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy. A putative retinoic acid response element was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (P < 0.05) with Cyp26a1 and Rarβ. These results show that Cyp2d mRNA is increased during mouse pregnancy the and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy. Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy.
Authors:
Ariel R Topletz; Huong N Le; Nora Lee; John D Chapman; Edward J Kelly; Joanne Wang; Nina Isoherranen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-13
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  41     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-07-12     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  312-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Cytochrome P-450 Enzyme System / biosynthesis*,  genetics*
Dextromethorphan / metabolism
Dextrorphan / metabolism
Enzyme Induction
Female
Hydroxylation
Liver / enzymology*
Mice
Models, Animal
Pregnancy
RNA, Messenger / biosynthesis*
Receptors, Retinoic Acid / biosynthesis,  genetics
Response Elements
Substrate Specificity
Tretinoin / metabolism
Grant Support
ID/Acronym/Agency:
R01GM081569/GM/NIGMS NIH HHS; TL1 TR000422/TR/NCATS NIH HHS; TL1TR000422/TR/NCATS NIH HHS; UL1 TR000423/TR/NCATS NIH HHS; UL1TR000423/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Cyp2d22 protein, mouse; 0/RNA, Messenger; 0/Receptors, Retinoic Acid; 0/retinoic acid receptor alpha; 0/retinoic acid receptor beta; 04B7QNO9WS/Dextrorphan; 5688UTC01R/Tretinoin; 7355X3ROTS/Dextromethorphan; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/CYP2D9 protein, mouse; EC 1.14.14.1/retinoic acid 4-hydroxylase
Comments/Corrections
Comment In:
Drug Metab Dispos. 2013 Feb;41(2):256-62   [PMID:  23328895 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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