A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity
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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2012
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| In: |
The journal of biological chemistry
Year: 2011, Volume: 287, Issue: 4, Pages: 2926-2934 |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M111.321281 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1074/jbc.M111.321281 Verlag, kostenfrei, Volltext: http://www.jbc.org/content/287/4/2926 
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| Author Notes: | Mototada Shichiri, Nozomu Kono, Yuta Shimanaka, Masaki Tanito, Daisy E. Rotzoll, Yasukazu Yoshida, Yoshihisa Hagihara, Hiroshi Tamai, and Hiroyuki Arai |
| Summary: | 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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| Item Description: | Published, JBC Papers in Press, December 6, 2011 Gesehen am 03.08.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M111.321281 |