Dataset Information

(-)-Epigallocatechin-3-gallate Inhibits Human and Rat Renal Organic Anion Transporters.

ABSTRACT: Organic anion transporter 1 (OAT1, SLC22A6) and 3 (OAT3, SLC22A8) are multispecific drug transporters highly expressed on the basolateral membranes of the renal proximal tubules. OAT1 and OAT3 mediate the tubular secretion of clinically significant drugs; thus, they influence the pharmacokinetics of drugs and further determine their efficacy and toxicity. OAT1 and OAT3 are also the target of drug-drug interactions. In this study, we examined the effects of the tea catechin (-)-epigallocatechin-3-gallate (EGCG) on human (h) and rat (r) OAT1 and OAT3 using the fluorescent organic anion 6-carboxyfluorescein (6-CF) and hOAT1-, hOAT3-, rOat1-, or rOat3-expressing HEK293 cells and on renal elimination of 6-CF in rats. 6-CF is transported by hOAT1, hOAT3, rOat1, and rOat3. 6-CF is urinary excreted by Oats in rats. EGCG, a dominant catechin in green tea leaf, inhibits human and rat OAT1 and OAT3 and reduces the renal elimination of 6-CF in rats. Our findings are useful for the assessment of food-drug interactions mediated by renal OATs.

SUBMITTER: Kawasaki T

PROVIDER: S-EPMC7893792 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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(-)-Epigallocatechin-3-gallate Inhibits Human and Rat Renal Organic Anion Transporters.

Kawasaki Tatsuya T Kondo Masaki M Hiramatsu Rioka R Nabekura Tomohiro T

ACS omega 20210202 6

Organic anion transporter 1 (OAT1, <i>SLC22A6</i>) and 3 (OAT3, <i>SLC22A8</i>) are multispecific drug transporters highly expressed on the basolateral membranes of the renal proximal tubules. OAT1 and OAT3 mediate the tubular secretion of clinically significant drugs; thus, they influence the pharmacokinetics of drugs and further determine their efficacy and toxicity. OAT1 and OAT3 are also the target of drug-drug interactions. In this study, we examined the effects of the tea catechin (-)-epig ...[more]

PMID: 33623845

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Project description:BackgroundEpigallocatechin gallate (EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine (DMH)-induced colorectal cancer (CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC.AimTo understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis.MethodsDMH (40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG (50, 100, or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG.ResultsAt week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors, tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210 (CRC), hsa04115 (p53 signaling pathway), and hsa04151 (PI3K-Akt signaling pathway), GO:0043124 (negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409 (negative regulation of mitogen-activated protein kinase cascade), and GO:2001244 (positive regulation of intrinsic apoptotic signaling pathway) respectively.ConclusionEGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis.

Project description:Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green tea in combinatorial treatments against active IBC disease or in maintenance regimens to avoid recurrence is warranted.

Dataset Information

(-)-Epigallocatechin-3-gallate Inhibits Human and Rat Renal Organic Anion Transporters.

Publications

(-)-Epigallocatechin-3-gallate Inhibits Human and Rat Renal Organic Anion Transporters.

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