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A novel role for ?-tocopherol transfer protein (?-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 ?-tocopherol transfer protein (?-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 ?-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 ?-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than ?-TTP transfectant cells. Similarly, ?-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, ?-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that ?-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport.

SUBMITTER: Shichiri M

PROVIDER: S-EPMC3268449 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity.

Shichiri Mototada M Kono Nozomu N Shimanaka Yuta Y Tanito Masaki M Rotzoll Daisy E DE Yoshida Yasukazu Y Hagihara Yoshihisa Y Tamai Hiroshi H Arai Hiroyuki H

The Journal of biological chemistry 20111206 4

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-TT ...[more]

PMID: 22147702

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Project description:BackgroundSalmonella enterica species are enteric pathogens that cause severe diseases ranging from self-limiting gastroenteritis to enteric fever and sepsis in humans. These infectious diseases are still the major cause of morbidity and mortality in low-income countries, especially in children younger than 5 years and immunocompromised adults. Vaccines targeting typhoidal diseases are already marketed, but none protect against non-typhoidal Salmonella. The existence of multiple non-typhoidal Salmonella serotypes as well as emerging antibiotic resistance highlight the need for development of a broad-spectrum protective vaccine. All Salmonella spp. utilize two type III Secretion Systems (T3SS 1 and 2) to initiate infection, allow replication in phagocytic cells and induce systemic disease. T3SS-1, which is essential to invade epithelial cells and cross the barrier, forms an extracellular needle and syringe necessary to inject effector proteins into the host cell. PrgI and SipD form, respectively, the T3SS-1 needle and the tip complex at the top of the needle. Because they are common and highly conserved in all virulent Salmonella spp., they might be ideal candidate antigens for a subunit-based, broad-spectrum vaccine.Principal findingsWe investigated the immunogenicity and protective efficacy of PrgI and SipD administered by subcutaneous, intranasal and oral routes, alone or combined, in a mouse model of Salmonella intestinal challenge. Robust IgG (in all immunization routes) and IgA (in intranasal and oral immunization routes) antibody responses were induced against both proteins, particularly SipD. Mice orally immunized with SipD alone or SipD combined with PrgI were protected against lethal intestinal challenge with Salmonella Typhimurium (100 Lethal Dose 50%) depending on antigen, route and adjuvant.Conclusions and significanceSalmonella T3SS SipD is a promising antigen for the development of a protective Salmonella vaccine, and could be developed for vaccination in tropical endemic areas to control infant mortality.

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A novel role for ?-tocopherol transfer protein (?-TTP) in protecting against chloroquine toxicity.

Publications

A novel role for α-tocopherol transfer protein (α-TTP) in protecting against chloroquine toxicity.

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