{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:36:04Z","timestamp":1791326164176,"version":"4.3.1"},"reference-count":52,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2013,9,1]],"date-time":"2013-09-01T00:00:00Z","timestamp":1377993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2013,9,1]],"date-time":"2013-09-01T00:00:00Z","timestamp":1377993600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Chloroquine (CQ) kills\n                    <jats:italic toggle=\"yes\">Plasmodium falciparum<\/jats:italic>\n                    by binding heme, preventing its detoxification to hemozoin in the digestive vacuole (DV) of the parasite. CQ resistance (CQR) is associated with mutations in the DV membrane protein\n                    <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                    chloroquine resistance transporter (PfCRT), mediating the leakage of CQ from the DV. However, additional factors are thought to contribute to the resistance phenotype. This study tested the hypothesis that there is a link between glutathione (GSH) and CQR.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    Using isogenic parasite lines carrying wild-type or mutant\n                    <jats:italic toggle=\"yes\">pfcrt<\/jats:italic>\n                    , we reveal lower levels of GSH in the mutant lines and enhanced sensitivity to the GSH synthesis inhibitor\n                    <jats:sc>l<\/jats:sc>\n                    -buthionine sulfoximine, without any alteration in cytosolic\n                    <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                    GSH synthesis. Incubation with\n                    <jats:italic toggle=\"yes\">N-<\/jats:italic>\n                    acetylcysteine resulted in increased GSH levels in all parasites, but only reduced susceptibility to CQ in PfCRT mutant-expressing lines. In support of a heme destruction mechanism involving GSH in CQR parasites, we also found lower hemozoin levels and reduced CQ binding in the CQR PfCRT-mutant lines. We further demonstrate\n                    <jats:italic toggle=\"yes\">via<\/jats:italic>\n                    expression in\n                    <jats:italic toggle=\"yes\">Xenopus laevis<\/jats:italic>\n                    oocytes that the mutant alleles of Pfcrt in CQR parasites selectively transport GSH.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:<\/jats:italic>\n                    <\/jats:bold>\n                    We propose a mechanism whereby mutant\n                    <jats:italic toggle=\"yes\">pfcrt<\/jats:italic>\n                    allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    PfCRT has a dual role in CQR, facilitating both efflux of harmful CQ from the DV and influx of beneficial GSH into the DV.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                    19, 683\u2013695.\n                  <\/jats:p>","DOI":"10.1089\/ars.2012.4625","type":"journal-article","created":{"date-parts":[[2012,12,20]],"date-time":"2012-12-20T10:17:53Z","timestamp":1355998673000},"page":"683-695","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":53,"title":["Glutathione Transport: A New Role for PfCRT in Chloroquine Resistance"],"prefix":"10.1177","volume":"19","author":[{"given":"Eva-Maria","family":"Patzewitz","sequence":"first","affiliation":[{"name":"University of Glasgow","place":["United Kingdom"]},{"name":"University of Nottingham","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Enrique","family":"Salcedo-Sora","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor H.","family":"Wong","sequence":"additional","affiliation":[{"name":"University of Glasgow","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Sethia","sequence":"additional","affiliation":[{"name":"University of Glasgow","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Stocks","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer C.","family":"Maughan","sequence":"additional","affiliation":[{"name":"Cardiff University","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.H.","family":"Murray","sequence":"additional","affiliation":[{"name":"Cardiff University","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev","family":"Krishna","sequence":"additional","affiliation":[{"name":"University of London","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick G.","family":"Bray","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylke","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"University of Glasgow","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2013,9,1]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","unstructured":"Atamna H and Ginsburg H. 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Chloroquine uptake and activity is determined by binding to ferriprotoporphyrin IX in Plasmodium falciparum. Novartis Found Symp 226: 252\u2013260; discussion 260\u2013254 1999."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","unstructured":"Bray PG Mungthin M Ridley RG and Ward SA. Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54: 170\u2013179 1998.","DOI":"10.1124\/mol.54.1.170"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","unstructured":"Cabrera M Natarajan J Paguio MF Wolf C Urbach JS and Roepe PD. Chloroquine transport in Plasmodium falciparum. 1. Influx and efflux kinetics for live trophozoite parasites using a novel fluorescent chloroquine probe. Biochemistry 48: 9471\u20139481 2009.","DOI":"10.1021\/bi901034r"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","unstructured":"Cabrera M Paguio MF Xie C and Roepe PD. Reduced digestive vacuolar accumulation of chloroquine is not linked to resistance to chloroquine toxicity. 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