In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines

Miyata, Kenichi; Nakagawa, Yoshiaki; Kimura, Yasuhisa; Ueda, Kazumitsu; Akamatsu, Miki

doi:10.1016/j.taap.2016.03.008

Cited by 9 publications

(5 citation statements)

References 48 publications

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“…At least 50 SNPs have been identified within MDR1 gene positions on chromosome 7, and the 3843 bp coding region comprises 28 exons (Sauna et al, 2007;Vine et al, 2014). Most importantly, among SNPs reported in the MDR1 gene, three insertion/deletion SNPs, C1236T in exon 12, G2677T/A in exon 21 and C3435T located in exon 26 respectively, have been most widely investigated and were determined to be functionally significant and ethnically found to be different when mapped at this region of gene (Kelland, 2007;Sharom, 2008;Miyata et al, 2016). Further, Hoffmeyer et al (2000) findings suggested that synonymous SNP C3435T in exon 26 plays an important role in the function of P-glycoprotein.…”

Section: Introductionmentioning

confidence: 99%

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer

et al. 2020

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Section: Introductionmentioning

confidence: 99%

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer

et al. 2020

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“…phospholipids, glycolipids, steroid hormones) and exogenous (e.g. anticancer drugs, anticonvulsants, anti-HIV drugs) substances from intra-to extracellular under consumption of ATP, protecting the body from toxins and xenobiotics [7][8][9]. Therefore, P-gp limits drug absorption, facilitates drug elimination and thus decreases the bioavailability of orally taken drugs [10].…”

mentioning

confidence: 99%

A Novel Model of P‐Glycoprotein Inhibitor Screening Using Human Small Intestinal Organoids

Zhao

Zeng

Sun

et al. 2016

Basic Clin Pharma Tox

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P-glycoprotein (P-gp), an important efflux transporter in intestine, regulates the bioavailability of orally taken drugs. To develop an in vitro model that preferably mimics the physiological microenvironment of human intestine, we employed the three-dimensionally (3D) cultured organoids from human normal small intestinal epithelium. It was observed that the intestinal crypts could efficiently form cystic organoid structure with the extension of culture time. Furthermore, the physiological expression of ABCB1 was detected at both mRNA and protein levels in cultured organoids. Rhodamine 123 (Rh123), a typical substrate of P-gp, was actively transported across 3D organoids and accumulated in the luminal space. This transport process was also inhibited by verapamil and mitotane. In summary, the above-mentioned model based on human small intestinal 3D organoids is suitable to imitate the small intestinal epithelium and could be used as a novel in vitro model especially for P-gp inhibitor screening.

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“…[ 15 ] Only three pesticides (ivermectin B1a, dimethomorph and spinosad) predicted in silico to be P‐gp inhibitors were confirmed by our in vitro assays with both MCF7R cell and Caco‐2 cell monolayer models. Nevertheless, predictions by our combination of web tools were correlated for other pesticides such as tebufenozide and methoxyfenozide, described as P‐gp inhibitors by a previous study, [ 33 ] but also imidacloprid and nitenpyram reported in vitro to be P‐gp noninhibitors. [ 18 ]…”

Section: Discussionmentioning

confidence: 91%

“…[15] Only three pesticides (ivermectin B1a, dimethomorph and spinosad) predicted in silico to be P-gp inhibitors were confirmed by our in vitro assays with both MCF7R cell and Caco-2 cell monolayer models. Nevertheless, predictions by our combination of web tools were correlated for other pesticides such as tebufenozide and methoxyfenozide, described as P-gp inhibitors by a previous study, [33] but also imidacloprid and nitenpyram reported in vitro to be P-gp noninhibitors. [18] We report here for the first time that cyflumetofen, fenpicoxamid, oxathiapiprolin, pinoxaden, profoxydim and silafluofen were not able to inhibit P-gp activity in vitro, these pesticides never having been evaluated previously to our knowledge.…”

Section: P-gp Activity Inhibition By Pesticides Based On the Apparent...mentioning

confidence: 96%

Combined in silico and in vitro approaches to identify P‐glycoprotein‐inhibiting pesticides

Guéniche,

Lakehal,

Habauzit

et al. 2023

J Biochem & Molecular Tox

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The P‐glycoprotein (P‐gp) efflux pump plays a major role in xenobiotic detoxification. The inhibition of its activity by environmental contaminants remains however rather little characterised. The present study was designed to develop a combination of different approaches to identify P‐gp inhibitors among a large number of pesticides using in silico and in vitro models. First, the prediction performance of four web tools was evaluated alone or in combination using a set of recently marketed drugs. The best combination of web tools—AdmetSAR2.0/PgpRules/pkCSM—was next used to predict P‐gp activity inhibition by 762 pesticides. Among the 187 pesticides predicted to be P‐gp inhibitors, 11 were tested in vitro for their ability to inhibit the efflux of reference substrates (rhodamine 123 and Hoechst 33342) in P‐gp overexpressing MCF7R cells and to inhibit the efflux of the reference substrate rhodamine 123 in the Caco‐2 cell monolayer. In MCF7R cell assays, ivermectin B1a, emamectin B1 benzoate, spinosad, dimethomorph and tralkoxydim inhibited P‐gp activity; ivermectin B1a, emamectin B1 benzoate and spinosad were determined to be stronger inhibitors (half‐maximal inhibitory concentration [IC50] of 3 ± 1, 5 ± 1 and 7 ± 1 µM, respectively) than dimethomorph and tralkoxydim (IC50 of 102 ± 7 and 88 ± 7 µM, respectively). Ivermectin B1a, emamectin B1 benzoate, spinosad and dimethomorph also inhibited P‐gp activity in Caco‐2 cell monolayer assays, with dimethomorph being a weaker P‐gp inhibitor. These combined approaches could be used to identify P‐gp inhibitors among food contaminants, but need to be optimised and adapted for high‐throughput screening.

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In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines

Cited by 9 publications

References 48 publications

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer

A Novel Model of P‐Glycoprotein Inhibitor Screening Using Human Small Intestinal Organoids

Combined in silico and in vitro approaches to identify P‐glycoprotein‐inhibiting pesticides

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