Glucuronidation in the caco-2 human intestinal cell line: Induction of UDP-glucuronosyltransferase 1∗6

Abid, Amr; Bouchon, Isabelle; Siest, Gérard; Sabolovic, Nicole

doi:10.1016/0006-2952(95)00162-s

Cited by 32 publications

(17 citation statements)

References 12 publications

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“…Interestingly, 7EC O-deethylation was up-regulated by BNF in all five experiments, i.e., also in the two experiments in which DMSO did not show any effect, which indicates that AhR-mediated induction can be detected in human intestinal slices. This finding is further strengthened by the observation that BNF induced CYP1A1 and UGT1A6 mRNA expression, which is in agreement with published findings with Caco-2 cells (Abid et al, 1995;Münzel et al, 2003).…”

Section: Induction In Human Intestinal Slicessupporting

confidence: 92%

Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro

et al. 2007

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ABSTRACT:Induction of drug enzyme activity in the intestine can strongly determine plasma levels of drugs. It is therefore important to predict drug-drug interactions in human intestine in vitro. We evaluated the applicability of human intestinal precision-cut slices for induction studies in vitro. Morphological examination and intracellular ATP levels indicated tissue integrity up to 24 h of incubation, whereas in proximal jejunum slices, the metabolic rate toward most substrates remained at 40 to 50% of initial values. In colon slices, the cytochrome P450 conversions were below the detection limit, but conjugation rates remained relatively constant during incubation. The inducibility of drug-metabolizing enzymes and P-glycoprotein was evaluated using prototypical inducers for five induction pathways. ␤-Naphthoflavone (aryl hydrocarbon receptor ligand) induced CYP1A1 (132-fold in colon and 362-fold in proximal jejunum) and UDP glucuronosyltransferase (UGT) 1A6 mRNA (9.8-fold in colon and 3.2-fold in proximal jejunum). In proximal jejunum, rifampicin (RIF) [pregnane X receptor (PXR) ligand] induced CYP3A4 (5.2-fold), CYP2B6 (2-fold), UGT1A6 (2.2-fold), and multidrug resistance-1 (MDR1)/ABCB1 mRNA (2.7-fold), whereas 6␤-hydroxytestosterone formation (CYP3A4) increased 2-fold. In colon, RIF induced UGT1A6 32-fold and MDR1 2.2-fold. Dexamethasone (glucocorticoid receptor and PXR ligand) induced CYP3A4 mRNA (3.5-fold) and activity (5-fold) in proximal jejunum. Phenobarbital (constitutive androstane receptor activator) induced CYP3A4 (4.1-fold, only in jejunum), CYP2B6 (4.9-fold in colon and 2.3-fold in proximal jejunum), and MDR1/ABCB1 mRNA and CYP3A4 activity (2-fold only proximal jejunum). Quercetin (nuclear factor-E2-related factor 2 activator) induced UGT1A6 mRNA (6.7-fold in colon and 2.2-fold in proximal jejunum). In conclusion, this study shows that human intestinal precision-cut slices are useful to study induction of drug-metabolizing enzymes and transporters in the human intestine.

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Section: Induction In Human Intestinal Slicessupporting

confidence: 92%

Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro

et al. 2007

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“…In this study, Caco-2 cells were used between passages 130-132, corresponding to maximal UGT activity [38]. Similar observations have been reported by Mizuma et al [39] with respect to the glucuronidation of 1-naphthol by Caco-2 cells.…”

Section: Discussionmentioning

confidence: 66%

Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Sabolovic

Humbert

Radominska‐Pandya

et al. 2006

Biopharm & Drug Disp

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Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene), a natural polyphenol present in grapes and peanuts, has been reported to exert a variety of potentially therapeutic effects. The aim of this study was to determine the contribution of the gastrointestinal (GI) tract to the glucuronidation of this compound and its cis-isomer, which also occurs naturally. For this purpose, glucuronidation of the two resveratrol isomers was investigated in human microsomes prepared from: stomach, duodenum, four segments of the remaining small intestine (S-1 to S-4) and colon, and from the human intestinal cell lines Caco-2 and PD-7. cis- and trans-Resveratrol were efficiently glucuronidated in the GI tract with the formation of both 3-O- and 4'-O-glucuronides, however, the two stereoisomers were glucuronidated at different rates depending on the donor and the segment considered. Microsomes prepared from Caco-2 and PD-7 cells also efficiently glucuronidated cis-resveratrol and, to a lesser extent, the trans-isomer, however, only the 3-O-glucuronide was formed. Among the UDP-glucuronosyltransferases (UGT) that are known to be expressed in the GI tract, the isoforms UGT1A1, 1A6, 1A8, 1A9 and 1A10 were active in glucuronidating trans- and/or cis-resveratrol. The results demonstrate that the GI tract may contribute significantly to the first pass metabolism of these naturally occurring polyphenols.

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“…The concentration dependence of induction was confirmed in experiments using 5, 10, 15, and 25 M apigenin, chrysin, and luteolin. Maximum induction of both UGT and CYP1A activity was reached with 25 M con- Münzel et al, 1999), 1-2 M 3-MC (Chung and Bresnick, 1994;Donato et al, 1995;Ritter et al, 1999;Runge et al, 2000), 2 mM phenobarbital (Doostdar et al, 1993;Donato et al, 1995;Ritter et al, 1999;Runge et al, 2000), 50 M ␤-naphthoflavone (Abid et al, 1995;Runge et al, 2000), 1 M dexamethasone (Doostdar et al, 1993;Donato et al, 1995), 50 M oltipraz (Ritter et al, 1999), and 50 M t-butylhydroquinone ]. The medium was changed every 24 h, and the cells were used for in situ metabolism assays 24 h after the last medium change.…”

Section: Methodsmentioning

confidence: 99%

“…Although induction of UGTs, interestingly, has a very low profile in review articles, several UGT isoforms have been shown to be inducible in human cell cultures. UGT1A6 and UGT1A9 have been shown to be regulated by aryl hydrocarbon receptor (AhR) agonists, such as ␤-naphthoflavone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Abid et al, 1995;Bock et al, 1999;Münzel et al, 1999), and UGT1A6, UGT1A9, and UGT2B7 by antioxidant type inducers, such as t-butylhydroquinone in Caco-2 cells. UGT1A1 has also been shown to be inducible mainly by 3-methylcholanthrene (3-MC) and to a small extent by phenobarbital and oltipraz in fresh human hepatocytes (Ritter et al, 1999).…”

mentioning

confidence: 99%

Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids—Structural Requirements

Walle¹,

Walle²

2002

Drug Metab Dispos

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ABSTRACT:Recent studies in our laboratory in the human hepatic and intestinal cell lines Hep G2 and Caco-2 have demonstrated induction of UGT1A1 by the flavonoid chrysin (5,7-dihydroxyflavone) using catalytic activity assays and Western and Northern blotting. In the present study, we examined which features of the flavonoid structures were associated with induction of UGT1A1 and whether common drug-metabolizing enzyme inducers also produce this induction. We also determined whether flavonoid treatment affected sulfate conjugation and CYP1A1 activity. We used intact Hep G2 cells for these studies, with chrysin as the model substrate. Both glucuronidation and sulfation were measured. Hep G2 cells were pretreated for 3 days with 25 M concentrations of 22 flavonoids (n ‫؍‬ 4-12). Only four flavonoids demonstrated induction of glucuronidation similar to that of chrysin (i.e., 3-5-fold in the intact cells).These were acacetin, apigenin, luteolin, and diosmetin, all of which, like chrysin, are 5,7-dihydroxyflavones with varying substituents in the B-ring. 5-Hydroxy-7-methoxyflavone and 5-methyl-7-hydroxyflavone produced a modest 1.5 to 2-fold induction, whereas all other flavonoids examined were without effect. None of the flavonoids caused more than a modest change in sulfation activity (60-140% of control). In contrast, all tested 5,7-dihydroxyflavones and -flavonols induced CYP1A1 activity (ethoxyresorufin deethylation). Of seven common drug-metabolizing enzyme inducers only 3-methylcholanthrene and oltipraz showed modest induction of chrysin glucuronidation but not 2,3,7,8-tetrachlorodibenzop-dioxin or phenobarbital. Together, these results strongly suggest that the flavonoid induction of UGT1A1 is through a novel nonaryl hydrocarbon receptor-mediated mechanism.

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Glucuronidation in the caco-2 human intestinal cell line: Induction of UDP-glucuronosyltransferase 1∗6

Cited by 32 publications

References 12 publications

Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro

Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine in Vitro

Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids—Structural Requirements

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