title: Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2.
abstract: Chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used to treat malaria and inflammatory diseases, long-term usage of which often causes severe side effects, especially retinopathy. Solute carrier transporters (SLCs) are important proteins responsible for the cellular uptake of endogenous and exogenous substances. Inhibitors competing with transporter substrates for SLCs often results in unfavorable toxicities and unsatisfactory therapeutic outcomes. We investigated the inhibitory effect of CQ and HCQ on substrate uptake mediated through a range of important SLC transporters in overexpressing human embryonic kidney (HEK293) cells. Our data revealed that both CQ and HCQ potently inhibit the uptake activity of organic anion transporting polypeptide 1A2 (OATP1A2). We recently reported OATP1A2 to be expressed in human retinal pigment epithelium (RPE), where it mediates cellular uptake of all-trans-retinol (atROL), a key step in the classical visual cycle. In this study, we demonstrate that CQ and HCQ could markedly impair atROL uptake in OATP1A2-expressing HEK293 cells and more importantly, in primary human RPE cells. Our study shows that CQ and HCQ are novel inhibitors of OATP1A2 and significantly impair OATP1A2-mediated substrate uptake, particularly transport of atROL into the RPE. This effect may compromise the function of the classic visual cycle leading to vision impairment and contribute to the retinopathy observed clinically in patients using CQ or HCQ.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, Australia.
authors.forename: Chenghao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Save Sight Institute, The University of Sydney, Sydney, Australia.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, Australia.
authors.forename: Ting
authors.initials: T
authors.lastname: Chan
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, Australia.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Lu
authors.affiliation: Save Sight Institute, The University of Sydney, Sydney, Australia.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Shen
authors.affiliation: Save Sight Institute, The University of Sydney, Sydney, Australia; School of Optometry and Vision Sciences, University of New South Wales, New South Wales 2052, Australia.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Madigan
authors.affiliation: Save Sight Institute, The University of Sydney, Sydney, Australia.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gillies
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, Australia. Electronic address: Fanfan.zhou@sydney.edu.au.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D027361:Organic Anion Transporters; C512988:SLCO1A2 protein, human; D006886:Hydroxychloroquine; D002738:Chloroquine
keywords: OATP1A2; chloroquine; drug interaction; hydroxychloroquine; inhibition; organic anion transporters; organic anion-transporting polypeptide transporters; organic cation transporters; solute carrier transporters