Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2

Ma, Ligeng; Qin, Yahong; Shen, Zhuowei; Bi, Huichang; Hu, Haiyong; Huang, Min; Zhou, Hui; Yu, Lushan; Jiang, Huidi; Zeng, Su

doi:10.1016/j.jep.2015.07.011

Cited by 15 publications

(12 citation statements)

References 32 publications

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“…These results imply that the basolateral-to-apical transport of AAI is mediated by BCRP, and not by P-gp or MRP2. In agreement, Ma et al [30] recently reported that AAI is a substrate of BCRP based on the finding that the basolateral-to-apical transport of AAI through BCRP-expressing LLC-PK 1 cell monolayers was much higher than the apical-to-basolateral transport of AAI, and a BCRP inhibitor decreased AAI transport through the monolayers. However, they reported the uptake of AAI from the apical membranes via passive diffusion, which is at variance with our previous study [29] and the present study (Tables 1 and 2).…”

Section: Discussionsupporting

confidence: 73%

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Effect of quercetin on the uptake and efflux of aristolochic acid I from Caco-2 cell monolayers

Kimura

Fujii

Haraguchi

et al. 2016

Journal of Pharmacy and Pharmacology

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Section: Discussionsupporting

confidence: 73%

“…However, the absorption mechanisms for AAI under neutral pH conditions (non‐H + ‐gradient conditions) have not yet been investigated. More recently, Ma et al . suggest the secretory transport of AAI via BCRP using Caco‐2 cell monolayers and BCRP‐expressing LLC‐PK 1 cell monolayers.…”

Section: Introductionmentioning

confidence: 99%

Effect of quercetin on the uptake and efflux of aristolochic acid I from Caco-2 cell monolayers

Kimura

Fujii

Haraguchi

et al. 2016

Journal of Pharmacy and Pharmacology

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“…The transporters BCRP and MDR1 belong to the multidrug resistance protein family. BCRP has recently been identified as an additional potential transporter in the elimination of mercury from proximal tubular cells (6), and aristolochic acid I is an additional substrate that is excreted by BCRP (43). The organ-and age-specific expression patterns of these transporters have been demonstrated in adult organs (44).…”

Section: Discussionmentioning

confidence: 99%

Age-associated differences in transporter gene expression in kidneys of male rats

Wang

et al. 2016

Molecular Medicine Reports

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Kidney transporters are involved in the secretion and reabsorption of endogenous and exogenous molecules. Numerous factors may influence their expression and affect drug disposition, efficacy and toxicity. The present study aimed to examine the development‑ and age‑associated variations in primary renal transporters in rats, including 6 uptake transporters: Organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 1, 2 and 3 and organic anion‑transporting polypeptide (OATP) 4C1, and 6 efflux transporters: Multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance‑associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2‑K. Kidneys from male Sprague Dawley rats during development (‑2, 1, 7, 14 and 21 days), maturation (28, 35 and 60 days) and aging (180, 540 and 850 days) were collected and total RNA was extracted, purified and subjected to reverse transcription‑quantitative polymerase chain reaction analysis. Total proteins were extracted for western blot analysis. OAT1 and 3, OCT1, BCRP, MRP2 and 4 and MATE2‑K expression levels were low in fetal kidneys, increased gradually following birth and markedly increased on maturation and adulthood. High levels were maintained until 850 days. OCT2, OATP4C1, Mdr1b and MATE1 expression levels were low in fetal kidneys, increased gradually following birth, and increased markedly on weaning, maturation and adulthood; however, levels were decreased on aging. OCT3 mRNA expression levels were low in fetal and newborn kidneys, and had two peaks at 35 and 850 days. The selected OAT1 and 3 and MDR1 protein expression levels revealed a similar expression pattern. Thus, kidney transporter expression is affected by ontogeny and aging, which may impact drug and toxicant disposition in children and the elderly.

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“…To further investigate the role of MRP2, accumulation experiments in MRP2-MDCK cells were performed as previously described [ 28 – 31 ]. Briefly, cells were seeded at a density of 2 × 10 5 cells/well on a 24-well plate.…”

Section: Methodsmentioning

confidence: 99%

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2

et al. 2019

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Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF’s active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5−100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC 50 value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells’ uptake of acyclovir and increased the plasma concentration.

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Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2

Cited by 15 publications

References 32 publications

Effect of quercetin on the uptake and efflux of aristolochic acid I from Caco-2 cell monolayers

Effect of quercetin on the uptake and efflux of aristolochic acid I from Caco-2 cell monolayers

Age-associated differences in transporter gene expression in kidneys of male rats

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2

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