Sulfation of hesperetin, naringenin and apigenin by the human cytosolic sulfotransferases: a comprehensive analysis

Daibani, Amal A. El; Xi, Yuecheng; Luo, Lijun; Mei, Xue; Zhou, Chun; Yasuda, Shin; Liu, Ming‐Cheh

doi:10.1080/14786419.2018.1503264

Cited by 7 publications

(3 citation statements)

References 31 publications

(29 reference statements)

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“…Sulfonation is an important phase II metabolism mediated by sulfotransferases (Kauffman, 2004;Dubaisi et al, 2019) and regulates the disposition of numerous endo-and xenobiotics (James and Ambadapadi, 2013;Garbacz et al, 2017). Moreover, we and other researchers have discovered that phenolic compounds, especially the flavonoids, are susceptible to glucuronidation and sulfonation (two important metabolic pathways) (Chen et al, 2014;Najmanova et al, 2019;El Daibani et al, 2020). Due to the attention, the glucuronide metabolite of formononetin has been identified and quantified in rat plasma after oral administration (Wang et al, 2014;Shi et al, 2015), which indicated that glucuronidation may be an important clearance mechanism for formononetin in vivo.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

Liu

Pei

et al. 2021

Front. Pharmacol.

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Formononetin is one of the main active compounds of traditional Chinese herbal medicine Astragalus membranaceus. However, disposition of formononetin via sulfonation pathway remains undefined. Here, expression-activity correlation was performed to identify the contributing of SULT1A3 to formononetin metabolism. Then the sulfonation of formononetin and excretion of its sulfate were investigated in SULT1A3 overexpressing human embryonic kidney 293 cells (or HKE-SULT1A3 cells) with significant expression of breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). As a result, formononetin sulfonation was significantly correlated with SULT1A3 protein levels (r = 0.728; p < 0.05) in a bank of individual human intestine S9 fractions (n = 9). HEK-SULT1A3 cells catalyzed formononetin formation of a monosulfate metabolite. Sulfate formation of formononetin in HEK-SULT1A3 cell lysate followed the Michaelis-Menten kinetics (Vmax = 13.94 pmol/min/mg and Km = 6.17 μM). Reduced activity of MRP4 by MK-571 caused significant decrease in the excretion rate (79.1%–94.6%) and efflux clearance (85.3%–98.0%) of formononetin sulfate, whereas the BCRP specific inhibitor Ko143 had no effect. Furthermore, silencing of MRP4 led to obvious decrease in sulfate excretion rates (>32.8%) and efflux clearance (>50.6%). It was worth noting that the fraction of dose metabolized (fmet), an indicator of the extent of drug sulfonation, was also decreased (maximal 26.7%) with the knockdown of MRP4. In conclusion, SULT1A3 was of great significance in determining sulfonation of formononetin. HEK-SULT1A3 cells catalyzed formononetin formation of a monosulfate. MRP4 mainly contributed to cellular excretion of formononetin sulfate and further mediated the intracellular sulfonation of formononetin.

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Section: Discussionmentioning

confidence: 99%

Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

Liu

Pei

et al. 2021

Front. Pharmacol.

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“…Hesperetin, the glycoside ligand derivative of hesperetin, exhibits good bioavailability (24). It has been demonstrated that hesperetin prevented 1,2-dimethylhydrazine-induced colorectal cancer (25,26) and induced apoptosis of colorectal cancer cells in a dose-dependent manner (27). The aim of the present study was to investigate the effects of hesperetin treatment on the sensitivity of A549/ddP cells to certain drugs.…”

Section: Introductionmentioning

confidence: 96%

Hesperetin reverses P‑glycoprotein‑mediated cisplatin resistance in DDP‑resistant human lung cancer cells via modulation of the nuclear factor‑κB signaling pathway

Kong¹,

Ling

Chen³

et al. 2020

Int J Mol Med

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Lung cancer is the leading cause of cancer-associated mortality worldwide. cisplatin (ddP) is a first-line chemotherapeutic drug for the treatment of lung cancer; however, the majority of patients develop resistance to ddP. P-glycoprotein (P-gp), also referred to as multidrug resistance (MdR) protein 1, is associated with an MdR phenotype, which results in failure of cancer chemotherapy; thus, identifying effective MdR pump inhibitors may improve the outcomes of patients who develop resistance to treatment. Hesperetin is a derivative of hesperidin, which is extracted from tangerine peel and exhibits multiple antitumor properties. In the present study, human lung adenocarcinoma A549 and A549/ddP cells were treated with different concentrations of hesperetin and DDP, respectively. Furthermore, rhodamine 123 efflux assays, cell counting Kit-8 assays, immunofluorescence, reverse transcription-quantitative PcR and western blot analysis were used to elucidate the mechanisms underlying the effects of hesperetin On A549/ddP cells. Additionally, a xenograft model of lung cancer in nude mice was established to explore the effects of hesperetin on A549/ddP cell growth in vivo. The results demonstrated that hesperetin sensitized A549/ddP cells to ddP. In vivo, hesperetin pretreatment significantly inhibited tumor growth. Mechanistically, hesperetin markedly decreased the expression of P-gp and increased the intracellular accumulation of the P-gp substrate, rhodamine 123, in A549/ddP cells. In addition, pretreatment of A549/ddP cells with hesperetin significantly inhibited nuclear factor (NF)-κB (p65) activity and its nuclear translocation. Taken together, the results of the present study suggest that hesperetin reversed P-gp-mediated MdR by decreasing P-gp expression in A549/ddP cells, which was associated with inhibition of the NF-κB signaling pathway. These findings may provide the basis for the use of hesperetin clinically to reverse MdR.

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“…Different enzymes, encoded by genes in human genome, are involved in phase II metabolism of flavanones. Among the sulfotransferases enzymes, SULT1A1, SULT1C4, and to a smaller extent SULT1E1 and SULT1A3, demonstrated the highest catalytic efficiencies for the sulfonation of hesperetin [18,19]. SULT1A1 has been described to sulfonate other flavonoids as well [20][21][22]; nevertheless, SULT1A1 only catalyzes the formation of hesperetin 3 -O-sulfate, whereas SULT1C4 solely catalyzes the formation of hesperetin 7-O-sulfate [18].…”

Section: Introductionmentioning

confidence: 99%

Association between Single Nucleotide Polymorphisms of SULT1A1, SULT1C4, ABCC2 and Phase II Flavanone Metabolites Excretion after Orange Juice Intake

et al. 2022

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Citrus fruits and juices are a major source of dietary flavanones, and the regular consumption of these foods is inversely associated with the development of cardiometabolic diseases. However, the biological benefits depend on the bioavailability of these compounds, and previous studies have reported a large interindividual variability in the absorption and excretion of these compounds. Different factors, such as age, gender or genetic polymorphism of genes coding enzymes involved in the metabolism and transport of the flavanones, may explain this heterogeneity. This study aimed to assess the impact of single nucleotide polymorphism of sulfotransferases SULT1A1 and SULT1C4, and ABCC2 transporter genes on excretion of phase II flavanone metabolites in volunteers after 24 h of orange juice intake. Forty-six volunteers ingested a single dose of 500 mL of orange juice and 24-h urine was collected. The hesperetin and naringenin phase II metabolites were quantified in urine, and SNPs in SULT1A1, SULT1C4 and ABCC2 genes were genotyped. A significant (p < 0.05) relationship between the SNPs in these genes and the high excretion of phase II flavanone metabolites were observed. These results identified novel polymorphisms associated with higher absorption of flavanones, which may provide bases for future personalized nutritional guidelines for consuming flavanone-rich foods rich in these nutrients for better benefit from their health properties.

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Sulfation of hesperetin, naringenin and apigenin by the human cytosolic sulfotransferases: a comprehensive analysis

Cited by 7 publications

References 31 publications

Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

Hesperetin reverses P‑glycoprotein‑mediated cisplatin resistance in DDP‑resistant human lung cancer cells via modulation of the nuclear factor‑κB signaling pathway

Association between Single Nucleotide Polymorphisms of SULT1A1, SULT1C4, ABCC2 and Phase II Flavanone Metabolites Excretion after Orange Juice Intake

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