Conjugation-deconjugation cycling of diflunisal via β-glucuronidase catalyzed hydrolysis of its acyl glucuronide in the rat

Brunelle, F M; Verbeeck, Roger K.

doi:10.1016/s0024-3205(97)00166-5

Cited by 19 publications

(9 citation statements)

References 23 publications

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“…Indeed, the phase II enzyme activities contribute to eliminating potential carcinogens, while b-glucuronidase is involved in recirculating glucurono-conjugates. 34,35 More precisely, we describe an enhancement of the speci®c activities of microsomal GST and UGTÐ 4MU (1.7-fold) in the caeco-colon. In the liver, only the speci®c activity of microsomal GST increased and the concentration of CYP450 remained unchanged.…”

Section: Discussionmentioning

confidence: 87%

The fermentation of lactulose in rats inoculated with Clostridium paraputrificum influences the activities of liver and intestinal xenobiotic‐metabolising enzymes

et al. 2001

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One of the most recent hypotheses concerning the protective effect of some dietary ®bres against colon cancer implicates butyrate. Very few publications have addressed its possible in¯uence on the phase II enzymes and on the bacterial enzymes involved in the enterohepatic recirculation of toxic compounds. We used an original model of monoxenic rats oriented towards the preferential production of butyrate. Fischer male germ-free rats were mono-associated with a strain of Clostridium paraputri®cum. They were fed either a control diet or a lactulose-enriched diet for 6 weeks. In the caeco-colon the speci®c activities (SAs) of the microsomal enzymes (glutathione-Stransferase and UDP-glucuronosyl-transferase) were 1.7-fold those of the control rats. In the intestine and liver the SAs of the phase II enzymes were not altered, nor was the hepatic cytochrome P450. In the caecum of the lactulose-fed rats the SA of b-glucuronidase decreased by 27% and that of b-glucosidase doubled. The chronic consumption of lactulose doubled the total caecal short-chain fatty acids, and the production of butyrate was enhanced. Since the germ-free rats behaved differently when fed the same diets, we concluded that the fermentation products of lactulose (and not the lactulose itself) were involved in the effects we describe. The involvement of butyrate in this phenomenon is discussed.

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Section: Discussionmentioning

confidence: 87%

The fermentation of lactulose in rats inoculated with Clostridium paraputrificum influences the activities of liver and intestinal xenobiotic‐metabolising enzymes

et al. 2001

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“…Hydrolysis might, however, occur intracellularly, followed by export of the resveratrol formed into the circulation by passive diffusion (Maier-Salamon et al, 2006) or via an as-yet-unidentified transporter. Intracellular deglucuronidation is not without precedent, because HepG2 cells can form quercetin from quercetin-glucuronide (O'Leary et al, 2003); moreover, diflunisal-glucuronides are deglucuronidated by rat liver during perfusion experiments (Brunelle and Verbeeck, 1997).…”

Section: Discussionmentioning

confidence: 99%

Intestinal Breast Cancer Resistance Protein (BCRP)/Bcrp1 and Multidrug Resistance Protein 3 (MRP3)/Mrp3 Are Involved in the Pharmacokinetics of Resveratrol

Wetering

Burkon²,

Feddema³

et al. 2008

Mol Pharmacol

113

104

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The phytoestrogen resveratrol has putative health-promoting effects and is present in several dietary constituents. Resveratrol is metabolized extensively in the gut epithelium, resulting in the formation of hydrophilic glucuronic acid and sulfate conjugates. These polar resveratrol conjugates need specific transporters to cross the cell membrane. We show here that vectorial transport of some of these metabolites is mediated by multidrug resistance protein 3 (MRP3, ABCC3) and/or breast cancer resistance protein (BCRP, ABCG2) located in the basolateral and apical membranes of enterocytes, respectively. In vitro, MRP3 transports resveratrol-glucuronide (Res-3-G). The absence of Mrp3 in mice results in altered disposition of Res-3-G and its parent compound resveratrol, leading to a reduced percentage of resveratrol being excreted via the urine in Mrp3(Ϫ/Ϫ) mice. Circumstantial evidence suggests that circulating resveratrol is formed by deglucuronidating Res-3-G in vivo, providing a possible explanation for the health beneficial effects of resveratrol in vivo, despite its rapid and extensive conjugation. BCRP transports Res-3-G and resveratrol sulfates in vitro, and its absence in mice results in high plasma levels of resveratrol-di-sulfate, a resveratrol metabolite hardly detectable in the plasma of wild-type mice and in an increased disposal of resveratrol via the urine. The profound effects of ATP-binding cassette transporters on the disposal of resveratrol may be representative for the handling of several other polyphenols of dietary origin.

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“…This can result in conjugation–deconjugation cycling that does not involve enterohepatic recirculation, as documented for the drug diflunisal. Treatment of rats with a specific β-glucuronidase inhibitor decreased metabolic clearance of diflunisal by 54% in experiments in which the bile duct was cannulated to prevent enterohepatic recirculation (Brunelle and Verbeeck 1997). Deconjugation of a variety of other xenobiotic metabolites has been documented in human liver preparations, including acetaminophen (Bohnenstengel et al 1999) and the aromatic amines benzidine and 4-aminobiphenyl (Zenser et al 1999).…”

Section: Why Rapid Metabolism Is Not the End Of The Storymentioning

confidence: 99%

Does Rapid Metabolism Ensure Negligible Risk from Bisphenol A?

Ginsberg

Rice²

2009

Environ Health Perspect

175

116

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BackgroundBisphenol A (BPA) risks are being evaluated by many regulatory bodies because exposure is widespread and the potential exists for toxicity at low doses.ObjectiveWe evaluated evidence that BPA is cleared more rapidly in humans than in rats in relation to BPA risk assessment.DiscussionThe European Food Safety Authority (EFSA) relied on pharmacokinetic evidence to conclude that rodent toxicity data are not directly relevant to human risk assessment. Further, the EFSA argues that rapid metabolism will result in negligible exposure during the perinatal period because of BPA glucuronidation in pregnant women or sulfation in newborns. These arguments fail to consider the deconjugation of BPA glucuronide in utero by β-glucuronidase, an enzyme that is present in high concentrations in placenta and various other tissues. Further, arylsulfatase C, which reactivates endogenous sulfated estrogens, develops early in life and so may deconjugate BPA sulfate in newborns. Biomonitoring studies and laboratory experiments document free BPA in rat and human maternal, placental, and fetal tissues, indicating that human BPA exposure is not negligible. The pattern of these detections is consistent with deconjugation in the placenta, resulting in fetal exposure. The tolerable daily intake set by the EFSA (0.05 mg/kg/day) is well above effect levels reported in some animal studies.ConclusionThis potential risk should not be dismissed on the basis of an uncertain pharmacokinetic argument. Rather, risk assessors need to decipher the BPA dose response and apply it to humans with comprehensive pharmacokinetic models that account for metabolite deconjugation.

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Conjugation-deconjugation cycling of diflunisal via β-glucuronidase catalyzed hydrolysis of its acyl glucuronide in the rat

Cited by 19 publications

References 23 publications

The fermentation of lactulose in rats inoculated with Clostridium paraputrificum influences the activities of liver and intestinal xenobiotic‐metabolising enzymes

The fermentation of lactulose in rats inoculated with Clostridium paraputrificum influences the activities of liver and intestinal xenobiotic‐metabolising enzymes

Intestinal Breast Cancer Resistance Protein (BCRP)/Bcrp1 and Multidrug Resistance Protein 3 (MRP3)/Mrp3 Are Involved in the Pharmacokinetics of Resveratrol

Does Rapid Metabolism Ensure Negligible Risk from Bisphenol A?

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