title: Time-Dependent Inhibition of hOAT1 and hOAT3 by Anthraquinones.
abstract: We previously showed that anthraquinones (including rhein, emodin, aloe-emodin, chrysophanol and physcion) were inhibitors of human organic anion transporter 1 (hOAT1) and hOAT3, causing transporter-mediated drug-drug interactions in rats. In this study, the time-dependent inhibition (TDI) of hOAT1 and hOAT3 by anthraquinones was investigated. Madin-Darby canine kidney (MDCK)-hOAT1, HEK293-hOAT3 and their parental cells were used. Preincubation with chrysophanol or physcion for 30 min significantly increased the inhibition of hOAT1, but preincubation with rhein, emodin, aloe-emodin or probenecid had no effect on hOAT1 activity. By contrast, preincubation of hOAT3 with emodin, aloe-emodin, chrysophanol or physcion for 30 min significantly increased its inhibition, but preincubation with rhein or probenecid had no effect on activity. As the incubating time lengthened, from 0 to 60 min, both the inhibition of hOAT1 by chrysophanol and physcion and the inhibition of hOAT3 by emodin, aloe-emodin, chrysophanol and physcion were observed to increase in a time-dependent manner. In conclusion, our results suggest that some anthraquinones contribute to the TDI of hOAT1 and hOAT3. An inhibition study without the preincubation procedure may underestimate the inhibitory potential of anthraquinones against hOAT1 and hOAT3. The underlying mechanisms of TDI of hOAT1 and hOAT3 need to be further investigated.
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University.
authors.forename: Liping
authors.initials: L
authors.lastname: Ma
authors.forename: Yahong
authors.initials: Y
authors.lastname: Qin
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Shen
authors.forename: Haihong
authors.initials: H
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.forename: Huidi
authors.initials: H
authors.lastname: Jiang
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3