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Research ArticleArticle

Genetic Variation in Aldo-Keto Reductase 1D1 (AKR1D1) Affects the Expression and Activity of Multiple Cytochrome P450s

Amarjit S. Chaudhry, Ranjit K. Thirumaran, Kazuto Yasuda, Xia Yang, Yiping Fan, Stephen C. Strom and Erin G. Schuetz
Drug Metabolism and Disposition August 2013, 41 (8) 1538-1547; DOI: https://doi.org/10.1124/dmd.113.051672
Amarjit S. Chaudhry
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Ranjit K. Thirumaran
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Kazuto Yasuda
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Xia Yang
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Yiping Fan
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Stephen C. Strom
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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Erin G. Schuetz
Departments of Pharmaceutical Sciences (A.S.C., R.K.T., K.Y., E.G.S.) and Computational Biology (Y.F.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Department of Integrative Biology and Physiology, University of California, Los Angeles, California (X.Y.); and Division of Pathology, Department of Laboratory Medicine, Karolinska Instituet, Stockholm, Sweden (S.C.S.)
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This article has a correction. Please see:

  • Correction to “Genetic Variation in Aldo-Keto Reductase 1D1 (AKR1D1) Affects the Expression and Activity of Multiple Cytochrome P450s” - May 01, 2014

Abstract

Human liver gene regulatory (Bayesian) network analysis was previously used to identify a cytochrome P450 (P450) gene subnetwork with Aldo-keto reductase 1D1 (AKR1D1) as a key regulatory driver of this subnetwork. This study assessed the biologic importance of AKR1D1 [a key enzyme in the synthesis of bile acids, ligand activators of farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), known transcriptional regulators of P450s] to hepatic P450 expression. Overexpression of AKR1D1 in primary human hepatocytes led to increased expression of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6. Conversely, AKR1D1 knockdown decreased expression of these P450s. We resequenced AKR1D1 from 98 donor livers and identified a 3′-untranslated region (UTR) (rs1872930) single nucleotide polymorphism (SNP) significantly associated with higher AKR1D1 mRNA expression. AKR1D1 3′-UTR-luciferase reporter studies showed that the variant allele resulted in higher luciferase activity, suggesting that the SNP increases AKR1D1 mRNA stability and/or translation efficiency. Consistent with AKR1D1’s putative role as a driver of the P450 subnetwork, the AKR1D1 3′-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple P450s (CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6) and CYP3A4, CYP2C8, CYP2C19, and CYP2B6 activities. After adjusting for multiple testing, the association remained significant for AKR1D1, CYP2C9, and CYP2C8 mRNA expression and CYP2C8 activity. These results provide new insights into the variation in expression and activity of P450s that can account for interindividual differences in drug metabolism/efficacy and adverse drug events. In conclusion, we provide the first experimental evidence supporting a role for AKR1D1 as a key genetic regulator of the P450 network.

Footnotes

    • Received February 19, 2013.
    • Accepted May 23, 2013.
  • dx.doi.org/10.1124/dmd.113.051672.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

AKR1D1 Polymorphism Affecting Multiple P450s

Amarjit S. Chaudhry, Ranjit K. Thirumaran, Kazuto Yasuda, Xia Yang, Yiping Fan, Stephen C. Strom and Erin G. Schuetz
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1538-1547; DOI: https://doi.org/10.1124/dmd.113.051672

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Research ArticleArticle

AKR1D1 Polymorphism Affecting Multiple P450s

Amarjit S. Chaudhry, Ranjit K. Thirumaran, Kazuto Yasuda, Xia Yang, Yiping Fan, Stephen C. Strom and Erin G. Schuetz
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1538-1547; DOI: https://doi.org/10.1124/dmd.113.051672
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