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Research ArticleArticle

Single-Nucleotide Polymorphisms in Cytochrome P450 2E1 (CYP2E1) 3′-Untranslated Region Affect the Regulation of CYP2E1 by miR-570

Masataka Nakano, Takuya Mohri, Tatsuki Fukami, Masataka Takamiya, Yasuhiro Aoki, Howard L. McLeod and Miki Nakajima
Drug Metabolism and Disposition October 2015, 43 (10) 1450-1457; DOI: https://doi.org/10.1124/dmd.115.065664
Masataka Nakano
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Takuya Mohri
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Tatsuki Fukami
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Masataka Takamiya
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Yasuhiro Aoki
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Howard L. McLeod
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Miki Nakajima
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Ma.N., T.M., T.F., Mi.N.); Department of Legal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan (M.T., Y.A.); Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri (H.L.M.)
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Abstract

Human cytochrome P450 2E1 (CYP2E1) catalyzes the metabolism of numerous xenobiotics, including acetaminophen and ethanol. CYP2E1 expression is known to be extensively regulated by post-transcriptional and post-translational mechanisms. A previous study had reported that a single-nucleotide polymorphism (SNP) 1561A>G in the 3′-untranslated region (3′-UTR) of CYP2E1 leads to a decreased CYP2E1 mRNA level in human peripheral blood mononuclear cells. In this study, we examined the possibility that microRNA(s) (miR) may be involved in the SNP-mediated modulation of CYP2E1 expression. Genotyping and sequencing analyses revealed that another SNP, 1556T>A, in the 3′-UTR was in complete linkage disequilibrium with the SNP 1561A>G. We termed the alleles with 1556T and 1561A or 1556A and 1561G haplotype I or II, respectively. A luciferase assay revealed that miR-570 recognizes the CYP2E1 3′-UTR of haplotype I but not haplotype II. Human embryonic kidney 293 (HEK293) cell lines stably expressing human CYP2E1 that included the 3′-UTR of haplotype I or II (HEK/2E1(I) or HEK/2E1(II) cells, respectively) were established. Overexpression of miR-570 significantly decreased the CYP2E1 protein level in the HEK/2E1(I) cells but not in the HEK/2E1(II) cells. In seven human livers with diplotype I/I, the CYP2E1 protein levels were inversely correlated with the miR-570 levels, but no relationship was observed in 25 human livers with diplotypes I/II and II/II. Collectively, it was demonstrated that human CYP2E1 was regulated by miR-570 in a genotype-dependent manner. This report describes the first proof that SNP in 3′-UTR of human P450 affects binding of miRNA to modulate the expression in the liver.

Footnotes

    • Received May 26, 2015.
    • Accepted July 21, 2015.
  • ↵1 Current affiliation: Department of Forensic Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Nagoya, Japan.

  • ↵2 Current affiliation: Moffitt Cancer Center, Tampa, Florida.

  • This work was supported by Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science [24390039].

  • dx.doi.org/10.1124/dmd.115.065664.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (10)
Drug Metabolism and Disposition
Vol. 43, Issue 10
1 Oct 2015
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Research ArticleArticle

Genotype-Dependent Regulation of Human CYP2E1 by miR-570

Masataka Nakano, Takuya Mohri, Tatsuki Fukami, Masataka Takamiya, Yasuhiro Aoki, Howard L. McLeod and Miki Nakajima
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1450-1457; DOI: https://doi.org/10.1124/dmd.115.065664

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Research ArticleArticle

Genotype-Dependent Regulation of Human CYP2E1 by miR-570

Masataka Nakano, Takuya Mohri, Tatsuki Fukami, Masataka Takamiya, Yasuhiro Aoki, Howard L. McLeod and Miki Nakajima
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1450-1457; DOI: https://doi.org/10.1124/dmd.115.065664
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