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Rapid CommunicationShort Communication

Cigarette Smoke Extract Induces CYP2B6 through Constitutive Androstane Receptor in Hepatocytes

Ikumi Washio, Makiko Maeda, Chika Sugiura, Ryota Shiga, Mitsuhiro Yoshida, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Drug Metabolism and Disposition January 2011, 39 (1) 1-3; DOI: https://doi.org/10.1124/dmd.110.034504
Ikumi Washio
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Makiko Maeda
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Chika Sugiura
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Ryota Shiga
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Mitsuhiro Yoshida
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Shinpei Nonen
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Yasushi Fujio
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Junichi Azuma
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences (I.W., C.S., R.S., Y.F., J.A.), and Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine (M.Y.), Osaka University, Osaka, Japan; and Department of Clinical Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan (M.M., S.N., J.A.)
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Abstract

Smoking induces a wide range of drug-metabolizing enzymes. Among them, CYP2B6 as well as CYP1A2 is well known to be up-regulated in smokers. Although the induction of CYP1A2 is mediated by the aryl hydrocarbon receptor, the molecular mechanisms of CYP2B6 induction by smoking remain to be fully elucidated. In this study, by preparing cigarette smoke extract (CSE), we addressed the possibility that human constitutive androstane receptor (hCAR) is involved in smoking-mediated induction of CYP2B6. In HepG2 cells, CSE induced CYP1A2 but not CYP2B6, suggesting that CYP2B6 expression is differentially regulated from CYP1A2. Compared with liver in vivo, hCAR expression is dramatically reduced in cultured hepatocytes, such as HepG2. Therefore, to reconstitute hCAR signaling pathways in vitro, we generated adenovirus vector expressing hCAR. Real-time reverse transcription-polymerase chain reaction analyses revealed that the adenoviral transfection of hCAR resulted in the up-regulation of CYP2B6 mRNA, even in the absence of CSE. It is interesting to note that CSE stimulation augmented hCAR-mediated induction of CYP2B6. In contrast, the expression of CYP2B6 was not enhanced by adenovirus vector expressing β-galactosidase, a control vector, either in the presence or absence of CSE. In summary, hCAR mediated the CYP2B6 induction by CSE in Hep2G cells. These data suggest that smoking up-regulates CYP2B6 through hCAR in vivo.

Footnotes

    • Received June 7, 2010.
    • Accepted October 18, 2010.
  • This work was supported in part by the Japanese Research Foundation for Clinical Pharmacology (to M.M.); and by Health and Labour Sciences Research Grants for Comprehensive Research on Cardiovascular and Life-Style Related Diseases (to M.M., S.N., Y.F., and J.A.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034504.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AhR
    aryl hydrocarbon receptor
    hCAR
    human constitutive androstane receptor
    Ad-hCAR
    adenovirus vector expressing hCAR
    CSE
    cigarette smoke extract
    PBS
    phosphate-buffered saline
    RT-PCR
    reverse transcription polymerase chain reaction
    HEK
    human embryonic kidney
    MOI
    multiplicity of infection
    Ad-βgal
    adenovirus vector expressing β-galactosidase.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Rapid CommunicationShort Communication

Cigarette Smoke Extract Induces CYP2B6 through Constitutive Androstane Receptor in Hepatocytes

Ikumi Washio, Makiko Maeda, Chika Sugiura, Ryota Shiga, Mitsuhiro Yoshida, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Drug Metabolism and Disposition January 1, 2011, 39 (1) 1-3; DOI: https://doi.org/10.1124/dmd.110.034504

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Cigarette Smoke Extract Induces CYP2B6 through Constitutive Androstane Receptor in Hepatocytes

Ikumi Washio, Makiko Maeda, Chika Sugiura, Ryota Shiga, Mitsuhiro Yoshida, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Drug Metabolism and Disposition January 1, 2011, 39 (1) 1-3; DOI: https://doi.org/10.1124/dmd.110.034504
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