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Tytuł:
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Adenosine N -methylation upregulates the expression of human CYP2B6 by altering the chromatin status.
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Autorzy:
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Isono M; DrugMetabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nakano M; DrugMetabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPINano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: .
Fukami T; DrugMetabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPINano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nakajima M; DrugMetabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPINano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: .
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Źródło:
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Biochemical pharmacology [Biochem Pharmacol] 2022 Nov; Vol. 205, pp. 115247. Date of Electronic Publication: 2022 Sep 13.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
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MeSH Terms:
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Chromatin*/genetics
Cytochrome P-450 CYP2B6*/genetics
Cytochrome P-450 CYP2B6*/metabolism
Humans ; Adenosine/pharmacology ; Adenosine/metabolism ; Bupropion ; Codon, Terminator ; Cytochrome P-450 CYP1A2/genetics ; Cytochrome P-450 CYP2C8/genetics ; Formaldehyde ; Histones/metabolism ; Methylation ; Methyltransferases/genetics ; Pregnane X Receptor/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Retinoid X Receptors/genetics ; Retinoid X Receptors/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
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Contributed Indexing:
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Keywords: CYP2B6; Chromatin status; Drug metabolism; Histone modification; P450; RNA methylation
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Substance Nomenclature:
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K72T3FS567 (Adenosine)
01ZG3TPX31 (Bupropion)
0 (Chromatin)
0 (Codon, Terminator)
EC 1.14.14.1 (CYP2B6 protein, human)
EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
EC 1.14.14.1 (Cytochrome P-450 CYP2B6)
EC 1.14.14.1 (Cytochrome P-450 CYP2C8)
1HG84L3525 (Formaldehyde)
0 (Histones)
EC 2.1.1.- (Methyltransferases)
EC 2.1.1.62 (METTL3 protein, human)
0 (Pregnane X Receptor)
0 (Receptors, Cytoplasmic and Nuclear)
0 (Retinoid X Receptors)
0 (RNA, Messenger)
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Entry Date(s):
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Date Created: 20220916 Date Completed: 20221024 Latest Revision: 20221129
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Update Code:
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20240105
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DOI:
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10.1016/j.bcp.2022.115247
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PMID:
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36113565
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N 6 -Methyladenosine (m 6 A) modification is the most prevalent RNA modification in mammals. We have recently demonstrated that inhibition of m 6 A modification by 3-deazaadenosine results in an increase in the expression of the cytochrome P450 (CYP) isoforms CYP1A2, CYP2B6, and CYP2C8 in human liver-derived cells. In the present study, we aimed to clarify the mechanism of m 6 A-mediated regulation of CYP2B6 expression. RNA immunoprecipitation using an anti-m 6 A antibody revealed that CYP2B6 mRNA in human liver and hepatocarcinoma-derived HepaRG cells was m 6 A-modified around the stop codon. In contrast to the treatment with 3-deazaadenosine, double knockdown of methyltransferase like (METTL) 3 and METTL14 (METTL3/14) resulted in a decrease in the levels of CYP2B6 mRNA in Huh-7 and HepaRG cells and a decrease in bupropion hydroxylase activity, a marker activity of CYP2B6, in HepaRG cells. The stability of CYP2B6 mRNA was not influenced by siMETTL3/14. Reporter assays using the plasmids containing the last exon or 5'-flanking region of CYP2B6 indicated that reporter activities were not influenced by knockdown of METTL3/14. The expression levels of the constitutive androstane receptor, pregnane X receptor, and retinoid X receptor, which are the nuclear receptors regulating the transcription of CYP2B6, were not influenced by siMETTL3/14. The chromatin immunoprecipitation and formaldehyde-assisted enrichment of regulatory elements assays revealed that H3K9me2, a repressive histone marker, was enriched in the vicinity of the upstream region of CYP2B6, and knockdown of METTL3/14 induced the condensation of the chromatin structure in this region. In conclusion, we demonstrated that METTL3/14 upregulated CYP2B6 expression by altering the chromatin status.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
