PMID- 23150428
OWN - NLM
STAT- MEDLINE
DCOM- 20130712
LR  - 20211021
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 41
IP  - 2
DP  - 2013 Feb
TI  - Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse 
      pregnancy.
PG  - 312-9
LID - 10.1124/dmd.112.049379 [doi]
AB  - 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)beta mRNA 
      (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rarbeta 
      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 Rarbeta. 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.
FAU - Topletz, Ariel R
AU  - Topletz AR
AD  - School of Pharmacy, Department of Pharmaceutics, University of Washington, 
      Seattle, WA 98195-7610, USA.
FAU - Le, Huong N
AU  - Le HN
FAU - Lee, Nora
AU  - Lee N
FAU - Chapman, John D
AU  - Chapman JD
FAU - Kelly, Edward J
AU  - Kelly EJ
FAU - Wang, Joanne
AU  - Wang J
FAU - Isoherranen, Nina
AU  - Isoherranen N
LA  - eng
GR  - UL1TR000423/TR/NCATS NIH HHS/United States
GR  - R01 GM081569/GM/NIGMS NIH HHS/United States
GR  - TL1 TR000422/TR/NCATS NIH HHS/United States
GR  - TL1TR000422/TR/NCATS NIH HHS/United States
GR  - UL1 TR000423/TR/NCATS NIH HHS/United States
GR  - R01 GM066233/GM/NIGMS NIH HHS/United States
GR  - R01GM081569/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121113
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (RARA protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Rara protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (retinoic acid receptor beta)
RN  - 04B7QNO9WS (Dextrorphan)
RN  - 5688UTC01R (Tretinoin)
RN  - 7355X3ROTS (Dextromethorphan)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (CYP2D9 protein, mouse)
RN  - EC 1.14.14.1 (Cyp26a1 protein, mouse)
RN  - EC 1.14.14.1 (Cyp2d22 protein, mouse)
RN  - EC 1.14.14.1 (Cytochrome P450 Family 2)
RN  - EC 1.14.14.1 (Retinoic Acid 4-Hydroxylase)
SB  - IM
CIN - Drug Metab Dispos. 2013 Feb;41(2):256-62. PMID: 23328895
MH  - Animals
MH  - Binding Sites
MH  - Cytochrome P-450 Enzyme System/*biosynthesis/*genetics
MH  - Cytochrome P450 Family 2
MH  - Dextromethorphan/metabolism
MH  - Dextrorphan/metabolism
MH  - Enzyme Induction
MH  - Female
MH  - Hydroxylation
MH  - Liver/*enzymology
MH  - Mice
MH  - Models, Animal
MH  - Pregnancy
MH  - RNA, Messenger/*biosynthesis
MH  - Receptors, Retinoic Acid/biosynthesis/genetics
MH  - Response Elements
MH  - Retinoic Acid 4-Hydroxylase
MH  - Retinoic Acid Receptor alpha
MH  - Substrate Specificity
MH  - Tretinoin/metabolism
PMC - PMC3558865
EDAT- 2012/11/15 06:00
MHDA- 2013/07/16 06:00
PMCR- 2014/02/01
CRDT- 2012/11/15 06:00
PHST- 2012/11/15 06:00 [entrez]
PHST- 2012/11/15 06:00 [pubmed]
PHST- 2013/07/16 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - dmd.112.049379 [pii]
AID - DMD_049379 [pii]
AID - 10.1124/dmd.112.049379 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2013 Feb;41(2):312-9. doi: 10.1124/dmd.112.049379. Epub 2012 
      Nov 13.