Expression Profiling of Sulfotransferases in Human Cell Lines Derived from Extra-Hepatic Tissues.

Tamura, Hiroomi; Taniguchi, Kenichi; Hayashi, Eriko; Hiyoshi, Yasuko; Nagai, Fusako

doi:10.1248/bpb.24.1258

Cited by 27 publications

(29 citation statements)

References 26 publications

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“…It also should be noted that, whereas glucuronidation of the unmethylated flavonoids in general predominated in the liver, sulfation was more important in the Caco-2 cells. This is consistent with previous observations and is dependent on tissue-specific expression of these enzymes (Glatt, 2000;Tamura et al, 2001).…”

Section: Discussionsupporting

confidence: 94%

Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability

2006

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ABSTRACT:To better understand the relationship between the chemical structure and biological fate of dietary polyphenols, the hepatic metabolic stability and intestinal absorption of methylated polyphenols, in comparison with unmethylated polyphenols, were investigated in pooled human liver S9 fraction and human colon adenocarcinoma (Caco-2) cells. Consistent with previous in vivo studies, the two well known unmethylated polyphenols resveratrol (3,5,4-trihydroxystilbene) and quercetin (3,5,7,3,4-pentahydroxyflavone) were rapidly eliminated by the S9 fraction in the presence of the appropriate cofactors for conjugation and oxidation. In contrast, the methylated flavones, i.e., 7-methoxyflavone, 7,4-dimethoxyflavone, 5,7-dimethoxyflavone, and 5,7,4-trimethoxyflavone, were relatively stable, indicating high resistance to hepatic metabolism. The corresponding unmethylated flavones, i.e., 7-hydroxyflavone, 7,4-dihydroxyflavone, chrysin (5,7-dihydroxyflavone), and apigenin (5,7,4-trihydroxyflavone), were rapidly eliminated because of extensive glucuronidation and/or sulfation just as resveratrol and quercetin were. The rate of intestinal absorption was evaluated using Caco-2 cells grown in porous inserts. The methylated flavones showed approximately 5-to 8-fold higher apparent permeability (P app , 22.6-27.6 ؋ 10 ؊6 cm s ؊1 ) of apical to basolateral flux than the unmethylated flavones (P app , 3.0-7.8 ؋ 10 ؊6 cm s ؊1 ). The lower P app values for the unmethylated flavones correlated with their extensive metabolism in the Caco-2 cells. Thus, combined use of the hepatic S9 fraction and Caco-2 cells will be useful for predicting the oral bioavailability of dietary polyphenols. The higher hepatic metabolic stability and intestinal absorption of the methylated polyphenols make them more favorable than the unmethylated polyphenols to be developed as potential cancer chemopreventive agents.

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Section: Discussionsupporting

confidence: 94%

Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability

2006

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“…After incubations of hesperetin with Caco-2 cell monolayers, formation of hesperetin 7-O-glucuronide and 7-O-sulfate was observed, whereas no metabolites of hesperetin conjugated at position 3Ј were detected. These observations could be explained by the relatively strong expression of SULT1C4 (Tamura et al, 2001;Meinl et al, 2008b) and UGT1A6 (Paine and Fisher, 2000), both enzymes specifically catalyzing the conjugation at position 7, compared with other SULT or UGT forms in Caco-2 cells. Moreover, small interfering RNA-mediated UGT1A6 silencing in this cell line heavily decreased the glucuronidation of the flavonoid apigenin, which demonstrates an important role for UGT1A6 in the glucuronidation by Caco-2 cells of a structurally related compound .…”

Section: Discussionmentioning

confidence: 99%

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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“…at ASPET Journals on May 10, 2018 dmd.aspetjournals.org published by Tamura et al (2001) on the expression of various SULT mRNA in Caco-2 cells. These findings will be discussed under Discussion.…”

Section: Sulfotransferase Expression In Caco-2 Cellsmentioning

confidence: 99%

“…Despite its origin from a tumor, the Caco-2 cell line has retained the ability to differentiate into polarized epithelial monolayers and shows numerous biochemical and morphological characteristics of enterocytes (e.g., formation of microvilli, tight junctions and desmosomes, and expression of brush-border enzymes such as sucrase-isomaltase) (Hidalgo et al, 1989). Caco-2 cells express various phase 1 and phase 2 enzymes, e.g., CYP1A1 (Boulenc et al, 1992) and CYP1B1 (Buesen et al, 2002;Lampen et al, 2004) and sulfotransferases 1A1 and 1A3 (Tamura et al, 2001), as well as transport proteins of the ATP-binding cassette family, such as P-glycoprotein (Hunter et al, 1993;Hirohashi et al, 2000), multidrug resistance-associated proteins, and breast cancer resistance protein (Taipalensuu et al, 2001). However, levels of transporters (Lennernas et al, 1996) and xenobiotic-metabolizing enzymes (Caro et al, 1995) may substantially vary from those found in intestine.…”

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confidence: 99%

Sulfotransferase Forms Expressed in Human Intestinal Caco-2 and TC7 Cells at Varying Stages of Differentiation and Role in Benzo[a]pyrene Metabolism

Meinl¹,

Ebert²,

Glatt³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The Caco-2 cell line and its subclone TC7 are frequently used for studying human intestinal transport and metabolism of xenobiotics. We have investigated the expression of soluble sulfotransferases (SULT) in parental Caco-2 and TC7 cells by immunoblotting. SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C1, SULT1C2, and SULT2A1 were expressed in both cell lines. SULT2B1a, SULT2B1b, and SULT4A1 were absent. SULT1E1 protein was found in TC7 but not in Caco-2 cells. Other differences in SULT between the cell lines were minor. More important was the influence of differentiation. Expression of the various SULT forms was low or not detectable in cultures just reaching confluence but then increased strongly. Likewise, the rate of sulfation of the model substrate 3-hydroxybenzo

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Expression Profiling of Sulfotransferases in Human Cell Lines Derived from Extra-Hepatic Tissues.

Cited by 27 publications

References 26 publications

Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability

Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability

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

Sulfotransferase Forms Expressed in Human Intestinal Caco-2 and TC7 Cells at Varying Stages of Differentiation and Role in Benzo[a]pyrene Metabolism

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