Document Detail


Gestational age-dependent changes in gene expression of metabolic enzymes and transporters in pregnant mice.
MedLine Citation:
PMID:  23175668     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pregnancy-induced changes in drug pharmacokinetics can be explained by changes in expression of drug-metabolizing enzymes and transporters and/or normal physiology. In this study, we determined gestational age-dependent expression profiles for all metabolic enzyme and transporter genes in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. We specifically examined the expression of genes important for xenobiotic, bile acid, and steroid hormone metabolism and disposition, namely, cytochrome P450s (Cyp), UDP-glucuronosyltranserases (Ugt), sulfotransferases (Sult), and ATP-binding cassette (Abc), solute carrier (Slc), and solute carrier organic anion (Slco) transporters. Few Ugt and Sult genes were affected by pregnancy. Cyp17a1 expression in the maternal liver increased 3- to 10-fold during pregnancy, which was the largest observed change in the maternal tissues. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 expression in the liver decreased on gestation days (gd) 15 and 19 compared with nonpregnant controls (gd 0). In contrast, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. In the placenta, Cyp expression on gd 10 and 15 was upregulated compared with gd 19. Notable changes were also observed in Abc and Slc transporters. Abcc3 expression in the liver and Abcb1a, Abcc4, and Slco4c1 expression in the kidney were downregulated on gd 15 and 19. In the placenta, Slc22a3 (Oct3) expression on gd 10 was 90% lower than that on gd 15 and 19. This study demonstrates important gestational age-dependent expression of metabolic enzyme and transporter genes, which may have mechanistic relevance to drug disposition in human pregnancy.
Authors:
Diana L Shuster; Theo K Bammler; Richard P Beyer; James W Macdonald; Jesse M Tsai; Frederico M Farin; Mary F Hebert; Kenneth E Thummel; Qingcheng Mao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-21
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:  332-42     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics,  metabolism*
Animals
Cytochrome P-450 Enzyme System / genetics,  metabolism*
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Enzymologic
Gestational Age
Glucuronosyltransferase / genetics,  metabolism*
Intestine, Small / enzymology*
Isoenzymes
Kidney / enzymology*
Liver / enzymology*
Mice
Oligonucleotide Array Sequence Analysis
Organic Anion Transporters / genetics,  metabolism*
Placenta / enzymology*
Pregnancy
Real-Time Polymerase Chain Reaction
Reproducibility of Results
Substrate Specificity
Sulfotransferases / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P30ES007033/ES/NIEHS NIH HHS; T32GM007750/GM/NIGMS NIH HHS; TL1 TR000422/TR/NCATS NIH HHS; U10HD047892/HD/NICHD NIH HHS; UL1 TR000423/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/Organic Anion Transporters; 9035-51-2/Cytochrome P-450 Enzyme System; EC 2.4.1.17/Glucuronosyltransferase; EC 2.8.2.-/Sulfotransferases
Comments/Corrections
Comment In:
Drug Metab Dispos. 2013 Feb;41(2):256-62   [PMID:  23328895 ]
Erratum In:
Drug Metab Dispos. 2013 Mar;41(3):682

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


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