Bisphenol a Glucuronidation and Excretion in Liver of Pregnant and Nonpregnant Female Rats

Inoue, Hiroki; Tsuruta, Akio; Kudo, S; Ishii, Takako; Fukushima, Yusuke; Iwano, Hidetomo; Yokota, Hiroshi; Kato, Shinichi

doi:10.1124/dmd.104.001537

Cited by 61 publications

(35 citation statements)

References 24 publications

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“…Similar functional changes in BPA conjugation have been reported in microsomes from pregnant rat livers (Matsumoto et al, 2002). In addition, BPA-glucuronide excretion into bile is reduced in pregnant rats due to downregulation of the multidrug resistance-associated protein 2 transporter (Inoue et al, 2005). It is likely that downregulation of BPA glucuronidation and transport may be the mechanisms governing reduced biliary excretion of BPA during pregnancy in rodents.…”

Section: Discussionsupporting

confidence: 50%

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Wen

Donepudi

Thomas

et al. 2012

J Pharmacol Exp Ther

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Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo-and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARa, and PXR and their target genes were downregulated, whereas ERa mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARa, PXR, and ERa signaling pathways may be candidate signaling pathways responsible for these changes.

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Section: Discussionsupporting

confidence: 50%

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Wen

Donepudi

Thomas

et al. 2012

J Pharmacol Exp Ther

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“…These studies demonstrated that the biliary excretion of the glucuronide conjugates of acetaminophen, phenobarbital, phenolphthalein, mycophenolic acid, bisphenol A, and valproic acid was nearly absent in Mrp2-deficient rats, whereas the sulfate metabolites, where relevant, were excreted at reduced levels (Xiong et al, 2000;Ogasawara and Takikawa, 2001;Chen et al, 2003;Patel et al, 2003;Tanaka et al, 2003;Kobayashi et al, 2004;Wright and Dickinson, 2004;Inoue et al, 2005). However, notable exceptions exist in this generally observed pattern of reduced phase II conjugate biliary excretion in Mrp2-deficient rats.…”

mentioning

confidence: 98%

Differential Involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in Biliary Excretion of 4-Methylumbelliferyl Glucuronide and Sulfate in the Rat

Zamek‐Gliszczynski¹,

Humphreys

Tian³

et al. 2006

J Pharmacol Exp Ther

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The hepatic excretion of hydrophilic conjugates, end products of phase II metabolism, is not completely understood. In the present studies, transport mechanism(s) responsible for the biliary excretion of 4-methylumbelliferyl glucuronide (4MUG) and 4-methylumbelliferyl sulfate (4MUS) were studied. Isolated perfused livers (IPLs) from Mrp2-deficient (TR Ϫ ) Wistar rats were used to examine the role of Mrp2 in the biliary excretion of 4MUG and 4MUS. After a 30-mol dose of 4-methylumbelliferone, cumulative biliary excretion of 4MUG was extensive in wild-type rat IPLs (25 Ϯ 3 mol) but was negligible in TR Ϫ livers (0.4 Ϯ 0.1 mol); coadministration of the Bcrp and P-glycoprotein inhibitor GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] had no effect on 4MUG biliary excretion in wild-type rat IPLs. In contrast, biliary excretion of 4MUS was partially maintained in Mrp2-deficient rat IPLs. Recovery of 4MUS in bile was ϳ50 to 60% lower in both control TR Ϫ (149 Ϯ 8 nmol) and wild-type IPLs with GF120918 coadministration (176 Ϯ 30 nmol) relative to wildtype control livers (378 Ϯ 37 nmol) and was nearly abolished in TR Ϫ IPLs in the presence of GF120918 (13 Ϯ 8 nmol). These changes were the result of decreased rate constants governing 4MUG and 4MUS biliary excretion. In vitro assays and perfused livers from Bcrp and P-glycoprotein gene-knockout mice indicated that 4MUS did not interact with P-glycoprotein but was transported by Bcrp in a GF120918-sensitive manner. In the rat liver, Mrp2 mediates the biliary excretion of 4MUG, whereas both Mrp2 and Bcrp contribute almost equally to the transport of 4MUS into bile.The liver is the primary site of xenobiotic detoxification in the body. Whereas substrates of hepatic metabolism may gain access to hepatocytes either by passive or carrier-mediated uptake, conjugation with a glucuronide or sulfate group results in a molecule with greatly decreased membrane permeability that requires active transport for hepatic excretion. Several transport proteins have been identified as efflux pumps for hepatic excretion of phase II metabolites (ZamekGliszczynski et al., 2006). Multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) are localized to the hepatic canalicular (apical) membrane, where they pump substrates into bile (Keppler and Konig, 1997;Maliepaard et al., 2001). Basolateral multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) are responsible for excretion of organic anions into sinusoidal blood for subsequent urinary excretion (Konig et al., 1999;Rius et al., 2003;Zelcer et al., 2003).Glucuronide and sulfate conjugates are typically watersoluble detoxification and inactivation products that are ex-

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“…Minimal mucosal excretion was observed in the colon. Inoue et al (2004) compared glucuronidation of bisphenol A in pregnant, non-pregnant, and male rats. Livers of 4 male and non-pregnant Sprague-Dawley rats/group were perfused via the portal vein for 1 hr with solutions containing bisphenol A at 10 or 50 mM [2.3 or 11 mg/L].…”

Section: Experimental Animalmentioning

confidence: 99%