Variable Sulfation of Dietary Polyphenols by Recombinant Human Sulfotransferase (SULT) 1A1 Genetic Variants and SULT1E1

Ung, Din; Nagar, Swati

doi:10.1124/dmd.106.013987

Cited by 55 publications

(44 citation statements)

References 37 publications

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“…SULT Isoform (Table 3). SULT1A1, SULT1A3, and SULT1E1 have been reported to sulfonate other flavonoids as well (Otake et al, 2002;Nakano et al, 2004;Ung and Nagar, 2007). In the present study, SULT1A1, SULT1A2, and SULT1E1 solely catalyzed the formation of hesperetin 3Ј-O-sulfate, whereas SULT1C4 and SULT2A1 solely catalyzed the formation of hesperetin 7-O-sulfate (Fig.…”

Section: Discussionmentioning

confidence: 54%

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

et al. 2010

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ABSTRACT:Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin (4-methoxy-3,5,7-trihydroxyflavanone). In the present study, we have determined the kinetics for glucuronidation and sulfonation of hesperetin by 12 individual UGT and 12 individual SULT enzymes as well as by human or rat small intestinal, colonic, and hepatic microsomal and cytosolic fractions. Results demonstrate that hesperetin is conjugated at positions 7 and 3 and that major enzyme-specific differences in kinetics and regioselectivity for the UGT and SULT catalyzed conjugations exist. UGT1A9, UGT1A1, UGT1A7, UGT1A8, and UGT1A3 are the major enzymes catalyzing hesperetin glucuronidation, the latter only producing 7-O-glucuronide, whereas UGT1A7 produced mainly 3-O-glucuronide. Furthermore, UGT1A6 and UGT2B4 only produce hesperetin 7-O-glucuronide, whereas UGT1A1, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15 conjugate both positions. SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3-O-sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7-O-sulfate. Based on expression levels SULT1A3 and SULT1B1 also will probably play a role in the sulfo-conjugation of hesperetin in vivo. The results help to explain discrepancies in metabolite patterns determined in tissues or systems with different expression of UGTs and SULTs, e.g., hepatic and intestinal fractions or Caco-2 cells. The incubations with rat and human tissue samples support an important role for intestinal cells during firstpass metabolism in the formation of hesperetin 3-O-glucuronide and 7-O-glucuronide, which appear to be the major hesperetin metabolites found in vivo.

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Section: Discussionmentioning

confidence: 54%

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

et al. 2010

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“…Sulfation reactions were conducted using HLC. In brief, by use of a modified assay (Ung and Nagar, 2007), a total incubation volume of 500 l contained 1 mg/ml HLC, 1 mM MCP, and 4 mM 3Ј-phosphoadenosine-5Ј-phosphosulfate in 10 mM potassium phosphate (pH 6.5). Incubations were performed for 3 h at 37°C and then terminated with ice-cold acetonitrile (200 l).…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Argikar

Gómez²,

Ung³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Metoclopramide (MCP) is frequently used to treat gastroparesis. Previous studies have documented MCP metabolism, but systematic structural identification of metabolites has not been performed. The aim of this study was to better understand MCP metabolism in humans. For examination of in vivo metabolism, a single oral 20-mg MCP dose was administered to eight healthy male volunteers, followed by complete urine collection over 24 h. In vitro incubations were performed in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 and UDPglucuronosyltransferases and in human liver cytosol for metabolism via sulfotransferases. Urine and subcellular incubations were analyzed for MCP metabolites on a mass spectrometer with accurate mass measurement capability.

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“…RES is extensively metabolized into its sulfated and glucuronidated metabolites, with trans-resveratrol-3-sulfate (R3S) and trans-resveratrol-3-glucuronide (R3G) as major metabolites (Juan et al, 2010;Iwuchukwu et al, 2012;Sharan et al, 2012). RES is sulfated mainly by SULT1A1 with minor contribution from SULT1E1 (Ung and Nagar, 2007). RES is glucuronidated at its 3-OH position via UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, and UGT2B7 (Brill et al, 2006).…”

Section: Pulmonary Metabolism Of Resveratrol: In Vitro and In Vivomentioning

confidence: 99%

“Target-Site” Drug Metabolism and Transport

et al. 2015

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The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic b-cell dysfunction and may have a role in how uremic toxins enter pancreatic b-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.

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Variable Sulfation of Dietary Polyphenols by Recombinant Human Sulfotransferase (SULT) 1A1 Genetic Variants and SULT1E1

Cited by 55 publications

References 37 publications

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

“Target-Site” Drug Metabolism and Transport

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