In vitro validation of drug-induced phospholipidosis

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Intracellular accumulation of phospholipids with lamellar bodies is a hallmark of drug-induced phospholipidosis (PLD) which is caused by impaired phospholipid metabolism of the lysosome. Although it remains uncertain whether PLD is associated with the adverse effects, sponsors generally terminate the development of a candidate drug when PLD is observed in an organ. For drugs that are used without serious adverse events, there should be labels indicating that the drug can induce PLD. We conducted LipidTox and NBD-PE assays for detecting PLD to compare and validate the methods. In the case of contrary results in both assays, electron microscopy was performed to confirm the data. We selected 12 chemicals and divided them into 4 categories: P+S+, PLD and steatosis positive; P+/S-, PLD positive and steatosis negative; P-S+, PLD negative and steatosis positive; P-/S-, PLD and steatosis negative. In general, results showed very good agreement with the known information with some minor discrepancies. LipidTox assay is proven to be a very sensitive method. Considering the contrary results of acetaminophen and menadione in LipidTox and the NBD-PE assay, the combination of two methods using different phospholipids is advantageous to reduce false positives. The finding that acetaminophen was positive in LipidTos assay and increased the frequency of lamellar body implies that acetaminophen is a weak inducer of PLD.

収録刊行物

  • Journal of toxicological sciences

    Journal of toxicological sciences 37(2), 261-267, 2012-04-01

    The Japanese Society of Toxicology

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各種コード

  • NII論文ID(NAID)
    10030126545
  • NII書誌ID(NCID)
    AN00002808
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    03881350
  • NDL 記事登録ID
    023673914
  • NDL 請求記号
    Z19-1022
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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