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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

Diana L. Shuster, Theo K. Bammler, Richard P. Beyer, James W. MacDonald, Jesse M. Tsai, Frederico M. Farin, Mary F. Hebert, Kenneth E. Thummel and Qingcheng Mao
Drug Metabolism and Disposition February 2013, 41 (2) 332-342; DOI: https://doi.org/10.1124/dmd.112.049718
Diana L. Shuster
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Theo K. Bammler
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Richard P. Beyer
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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James W. MacDonald
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Jesse M. Tsai
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Frederico M. Farin
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Mary F. Hebert
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Kenneth E. Thummel
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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Qingcheng Mao
Departments of Pharmaceutics (D.L.S., K.E.T., Q.M.) and Pharmacy (M.F.H.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington (T.K.B., R.P.B., J.W.M., J.M.T., F.M.F.); and Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington (M.F.H.)
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This article has a correction. Please see:

  • Correction to “Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice” - March 01, 2013

Abstract

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.

Footnotes

  • This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant U10HD047892]. This study was also supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P30ES007033] and by the National Institutes of Health Pharmacological Sciences Training Grant [Grant T32GM007750]. 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.

  • dx.doi.org/10.1124/dmd.112.049718

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received October 16, 2012.
  • Accepted November 21, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Gestational Changes in Metabolic Enzyme and Transport Genes

Diana L. Shuster, Theo K. Bammler, Richard P. Beyer, James W. MacDonald, Jesse M. Tsai, Frederico M. Farin, Mary F. Hebert, Kenneth E. Thummel and Qingcheng Mao
Drug Metabolism and Disposition February 1, 2013, 41 (2) 332-342; DOI: https://doi.org/10.1124/dmd.112.049718

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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Gestational Changes in Metabolic Enzyme and Transport Genes

Diana L. Shuster, Theo K. Bammler, Richard P. Beyer, James W. MacDonald, Jesse M. Tsai, Frederico M. Farin, Mary F. Hebert, Kenneth E. Thummel and Qingcheng Mao
Drug Metabolism and Disposition February 1, 2013, 41 (2) 332-342; DOI: https://doi.org/10.1124/dmd.112.049718
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