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Research ArticleArticle

Toxicological Evaluation of Acyl Glucuronides of Nonsteroidal Anti-Inflammatory Drugs Using Human Embryonic Kidney 293 Cells Stably Expressing Human UDP-Glucuronosyltransferase and Human Hepatocytes

Toshihisa Koga, Ryoichi Fujiwara, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition January 2011, 39 (1) 54-60; DOI: https://doi.org/10.1124/dmd.110.035600
Toshihisa Koga
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
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Ryoichi Fujiwara
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
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Miki Nakajima
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
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Tsuyoshi Yokoi
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
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Abstract

The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence that AG formation was related to the toxicity. In the present study, the cytotoxicity and genotoxicity of AGs were investigated. Human embryonic kidney (HEK) 293 cells stably expressing UDP-glucuronosyltransferase (UGT) 1A3 (HEK/UGT1A3) were constructed to assess the cytotoxicity of AGs, and HEK/UGT1A4 cells were also used as a negative reference. After exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen (1 mM), diclofenac (0.1 mM), ketoprofen (1 mM), or ibuprofen (1 mM) for 24 h, HEK/UGT1A3 cells produced AG in a time-dependent manner. However, HEK/UGT1A4 cells hardly produced AG. The cytotoxicity of HEK/UGT1A3 cells was not increased compared with that of HEK/UGT1A4 cells. In addition, the AG formed in NSAID-treated human hepatocytes was decreased from one-third to one-ninth by treatment with (−)-borneol, an inhibitor of acyl glucuronidation, but the cytotoxicity was increased. These results indicated that AG formation reflected the detoxification process in human hepatocytes. Furthermore, the possibility of genotoxicity from the AG formed in NSAID-treated HEK/UGT cells was investigated by the comet assay, and DNA damage was not detected in any HEK/UGT cell lines. In conclusion, the in vitro cytotoxic and genotoxic effects of the AGs of NSAIDs were investigated and AG was not found to be a causal factor in the toxicity.

Footnotes

    • Received July 23, 2010.
    • Accepted October 6, 2010.
  • This study was supported by the Ministry of Health, Labor, and Welfare of Japan [Health and Labor Sciences Research Grant H20-B10-G001].

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

    doi:10.1124/dmd.110.035600.

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

  • ABBREVIATIONS:

    NSAID
    nonsteroidal anti-inflammatory drug
    AG
    acyl glucuronide
    UGT
    UDP-glucuronosyltransferase
    HEK
    human embryonic kidney
    DMSO
    dimethyl sulfoxide
    UDPGA
    UDP-glucuronic acid
    4-MU
    4-methylumbelliferone
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    PAGE
    polyacrylamide gel electrophoresis
    PBS
    phosphate-buffered saline
    HPLC
    high-performance liquid chromatography
    FBS
    fetal bovine serum
    DMEM
    Dulbecco's modified Eagle's medium
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    WST-8
    2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium monosodium salt
    LDH
    lactic dehydrogenase.

  • 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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Research ArticleArticle

Toxicological Evaluation of Acyl Glucuronides of Nonsteroidal Anti-Inflammatory Drugs Using Human Embryonic Kidney 293 Cells Stably Expressing Human UDP-Glucuronosyltransferase and Human Hepatocytes

Toshihisa Koga, Ryoichi Fujiwara, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition January 1, 2011, 39 (1) 54-60; DOI: https://doi.org/10.1124/dmd.110.035600

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Research ArticleArticle

Toxicological Evaluation of Acyl Glucuronides of Nonsteroidal Anti-Inflammatory Drugs Using Human Embryonic Kidney 293 Cells Stably Expressing Human UDP-Glucuronosyltransferase and Human Hepatocytes

Toshihisa Koga, Ryoichi Fujiwara, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition January 1, 2011, 39 (1) 54-60; DOI: https://doi.org/10.1124/dmd.110.035600
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