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A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity
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| Veröffentlicht in: | The journal of biological chemistry 287(2012), 4, Seite 2926-2934 |
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| Personen und Körperschaften: | , |
| Titel: | A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity/ Mototada Shichiri, Nozomu Kono, Yuta Shimanaka, Masaki Tanito, Daisy E. Rotzoll, Yasukazu Yoshida, Yoshihisa Hagihara, Hiroshi Tamai, and Hiroyuki Arai |
| Format: | E-Book-Kapitel |
| Sprache: | Englisch |
| veröffentlicht: |
2012
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| Gesamtaufnahme: |
: The journal of biological chemistry, 287(2012), 4, Seite 2926-2934
, volume:287 |
| Schlagwörter: | |
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
| Zusammenfassung: | Chloroquine (CQ) is a widely prescribed anti-malarial agent and is also prescribed to treat autoimmune diseases. Clinical treatment with CQ is often accompanied by serious side effects such as hepatitis and retinopathy. As a weak base, CQ accumulates in intracellular acidic organelles, raises the pH, and induces osmotic swelling and permeabilization of acidic organelles, which account for CQ-induced cytotoxicity. We reported previously that CQ treatment caused α-tocopherol transfer protein (α-TTP), a gene product of familial vitamin E deficiency, to change its location from the cytosol to the surface of acidic organelles. Here we show that α-TTP plays a novel role in protecting against CQ toxicity both in vitro and in vivo. In the presence of CQ, rat hepatoma McARH7777 cells, which do not express α-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than α-TTP transfectant cells. Similarly, α-TTP knockout mice showed more severe CQ toxicity, such as hepatotoxicity and retinopathy, than wild-type mice. These effects were not ameliorated by vitamin E supplementation. In contrast to bafilomycin A1 treatment, which prevents CQ accumulation in cells by raising the pH of acidic organelles, α-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that α-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport. |
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| Beschreibung: |
Published, JBC Papers in Press, December 6, 2011 Gesehen am 03.08.2018 |
| Umfang: | 9 |
| ISSN: |
1083-351X
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| DOI: | 10.1074/jbc.M111.321281 |