| First Author | Shichiri M | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 4 | Pages | 2926-34 |
| PubMed ID | 22147702 | Mgi Jnum | J:181519 |
| Mgi Id | MGI:5311543 | Doi | 10.1074/jbc.M111.321281 |
| Citation | Shichiri M, et al. (2012) A novel role for alpha-tocopherol transfer protein (alpha-TTP) in protecting against chloroquine toxicity. J Biol Chem 287(4):2926-34 |
| abstractText | 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 alpha-tocopherol transfer protein (alpha-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 alpha-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 alpha-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than alpha-TTP transfectant cells. Similarly, alpha-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, alpha-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that alpha-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport. |
