title: A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity.
abstract: 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.
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Mototada
authors.initials: M
authors.lastname: Shichiri
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kono
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shimanaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanito
authors.forename: Daisy E
authors.initials: DE
authors.lastname: Rotzoll
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hagihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism; D002738:Chloroquine / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D003600:Cytosol; D003603:Cytotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D015388:Organelles / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D012164:Retinal Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D002352:Carrier Proteins; D003603:Cytotoxins; C017763:alpha-tocopherol transfer protein; D002738:Chloroquine