Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue

Miaoran Ning; Julio D. Duarte; Faith Stevison; Nina Isoherranen; Leah H. Rubin; Hyunyoung Jeong

doi:10.1111/cts.12632

Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue

Miaoran Ning, Julio D. Duarte, Faith Stevison, Nina Isoherranen, Leah H. Rubin, Hyunyoung Jeong

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme that exhibits large interindividual variability. Recent studies suggest that differential transcriptional regulation of CYP2D6 in part may be responsible for the variability. In this study, we characterized potential determinants of CYP 2D6 transcript levels in healthy human liver tissue samples (n = 115), including genetic polymorphisms in CYP2D6 and the genes encoding transcription regulators for CYP2D6 expression; mRNA expression of the transcription factors and their known target genes; and hepatic levels of bile acids and retinoids, agents that modulate the expression/activity of the transcription factors. Their associations with CYP2D6 mRNA levels in the tissues were examined. Results from multivariable linear regression analysis revealed CYP8B1 mRNA level and rs3892097, the single- nucleotide polymorphism defining the nonfunctional CYP2D6*4 allele, as the two most significant predictors of CYP2D6 mRNA levels in the liver tissue samples, explaining 30% of the variability.

Original language	English (US)
Pages (from-to)	416-423
Number of pages	8
Journal	Clinical and translational science
Volume	12
Issue number	4
DOIs	https://doi.org/10.1111/cts.12632
State	Published - Jul 2019

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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title = "Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue",

abstract = "Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme that exhibits large interindividual variability. Recent studies suggest that differential transcriptional regulation of CYP2D6 in part may be responsible for the variability. In this study, we characterized potential determinants of CYP 2D6 transcript levels in healthy human liver tissue samples (n = 115), including genetic polymorphisms in CYP2D6 and the genes encoding transcription regulators for CYP2D6 expression; mRNA expression of the transcription factors and their known target genes; and hepatic levels of bile acids and retinoids, agents that modulate the expression/activity of the transcription factors. Their associations with CYP2D6 mRNA levels in the tissues were examined. Results from multivariable linear regression analysis revealed CYP8B1 mRNA level and rs3892097, the single- nucleotide polymorphism defining the nonfunctional CYP2D6*4 allele, as the two most significant predictors of CYP2D6 mRNA levels in the liver tissue samples, explaining 30% of the variability.",

author = "Miaoran Ning and Duarte, {Julio D.} and Faith Stevison and Nina Isoherranen and Rubin, {Leah H.} and Hyunyoung Jeong",

note = "Funding Information: Funding. This work was supported by National Institutes of Health (NIH) (grants R01 GM112746 and R01 HD089455) and in part by a Graduate Student Fellowship Award from the American Association of Pharmaceutical Scientists Foundation (to M.N.). J.D.D. and F.S. were supported by the NIH (K23 GM112014 and T32 GM007750, respectively). Publisher Copyright: {\textcopyright} 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.",

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AU - Rubin, Leah H.

AU - Jeong, Hyunyoung

N1 - Funding Information: Funding. This work was supported by National Institutes of Health (NIH) (grants R01 GM112746 and R01 HD089455) and in part by a Graduate Student Fellowship Award from the American Association of Pharmaceutical Scientists Foundation (to M.N.). J.D.D. and F.S. were supported by the NIH (K23 GM112014 and T32 GM007750, respectively). Publisher Copyright: © 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

PY - 2019/7

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N2 - Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme that exhibits large interindividual variability. Recent studies suggest that differential transcriptional regulation of CYP2D6 in part may be responsible for the variability. In this study, we characterized potential determinants of CYP 2D6 transcript levels in healthy human liver tissue samples (n = 115), including genetic polymorphisms in CYP2D6 and the genes encoding transcription regulators for CYP2D6 expression; mRNA expression of the transcription factors and their known target genes; and hepatic levels of bile acids and retinoids, agents that modulate the expression/activity of the transcription factors. Their associations with CYP2D6 mRNA levels in the tissues were examined. Results from multivariable linear regression analysis revealed CYP8B1 mRNA level and rs3892097, the single- nucleotide polymorphism defining the nonfunctional CYP2D6*4 allele, as the two most significant predictors of CYP2D6 mRNA levels in the liver tissue samples, explaining 30% of the variability.

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Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue

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