Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate

Trottier, Jocelyn; Perreault, Martin; Rudkowska, Iwona; Levy, Cynthia; Dallaire-Theroux, Amélie; Verreault, Mélanie; Caron, Patrick; Staels, Bart; Vohl, Marie‐Claude; Straka, Robert J.; Barbier, Olivier

doi:10.1038/clpt.2013.122

Cited by 41 publications

(64 citation statements)

References 47 publications

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“…Samples were frozen and kept at −80°C until processed. Bile acids were purchased from Steraloids (Newport, RI), whereas glucuronidated acids were produced as previously reported . Deuterated isotopes used as analytical standards were from C/D/N Isotopes, Inc. (Pointe‐Claire, Québec, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis

et al. 2014

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Ursodeoxycholic acid (UDCA) is no longer recommended for management of adult patients with primary sclerosing cholangitis (PSC). We undertook a prospective evaluation of UDCA withdrawal in a group of consecutive patients with PSC. Twenty six patients, all treated with UDCA (dose range: 10-15 mg/kg/day) were included. Paired blood samples for liver biochemistry, bile acids, and fibroblast growth factor 19 (FGF19) were collected before UDCA withdrawal and 3 months later. Liquid chromatography/tandem mass spectrometry was used for quantification of 29 plasma bile acid metabolites. Pruritus and health-related quality of life (HRQoL) were assessed with a 10-point numeric rating scale, the Medical Outcomes Study Short Form-36 (SF-36), and PBC-40 questionnaires. UDCA withdrawal resulted in a significant deterioration in liver biochemistry (increase of alkaline phosphatase of 75.6%; P < 0.0001; gamma-glutamyl transpeptidase of 117.9%, P < 0.0001; bilirubin of 50.0%, P < 0.001; alanine aminotransferase of 63.9%, P < 0.005; and aspartate aminotransferase of 45.0%, P < 0.005) and increase of Mayo Risk Score for PSC (change from baseline of 10.5 point; P < 0.003). Bile acid analysis revealed a significant decrease in lithocholic acid and its derivatives after UDCA withdrawal, but no effect on concentrations of primary bile acids aside from an increased accumulation of their taurine conjugates. After UDCA removal cholestatic parameters, taurine species of cholic acid and chenodeoxycholic acid correlated with serum FGF19 levels. No significant effect on HRQoL after UDCA withdrawal was observed; however, 42% of patients reported a deterioration in their pruritus. Conclusion: At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites. A proportion of patients report increased pruritus, but other short-term markers of quality of life are unaffected. (HEPATOLOGY 2014;60:931-940)

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Section: Methodsmentioning

confidence: 99%

“…Deuterated isotopes used as analytical standards were from C/D/N Isotopes, Inc. (Pointe‐Claire, Québec, Canada). For bile acid/glucuronide metabolites, deuterated standards were synthesized as previously described . All chemicals and solvents were of the highest grade.…”

Section: Methodsmentioning

confidence: 99%

Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis

et al. 2014

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“…Consequently, it is not surprising that gallbladder bile, liver tissue, serum, and urine samples render complex, and distinctive, BA signature profiles (Takikawa et al, 1985;Rossi et al, 1987;Hamilton et al, 2007;Garcia-Canaveras et al, 2012;Humbert et al, 2012;Trottier et al, 2013). Such "signatures" are reflective of the PK-ADME properties of individual BAs (Table 1), imparted by their unique transporter-enzyme-NHR profile [e.g., BSEP-sodium-taurocholate cotransporting polypeptide (NTCP)-organic anion transporting peptide (OATP)-multidrug resistance-associated protein 2 (MRP-2)-farnesoid X receptor (FXR)-SULT2A1] (Heuman et al, 1989;Meier et al, 1997;Parks et al, 1999;Staudinger et al, 2001;Hayashi et al, 2005;Huang et al, 2010).…”

Section: Major Considerationsmentioning

confidence: 99%

“…f Not reported. g Trottier et al (2013) report that 38% of serum CDCA is in the form of 3-O-glucuronide (amidated vs. nonamidated not specified). The same authors report that about 14% of serum CA is in the form of an acyl glucuronide (nonamidated).…”

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confidence: 99%

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

et al. 2013

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The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3-or ATPase-aminophospholipid transporter-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.

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“…UGT2B7 is an enzyme responsible for detoxification of xenobiotics, including drugs such as morphine, efavirenz, zidovudine, and fenofibric acid, and is involved in the homeostasis of endogenous molecules like eicosanoids, bile acids, and sex steroids (Jin et al, 1997;Barbier et al, 2000;Stone et al, 2003;Turgeon et al, 2003;Thibaudeau et al, 2006;Mano et al, 2007;Bélanger et al, 2009;Tojcic et al, 2009;Trottier et al, 2013). Its expression is high in liver and kidney, but is also detectable in the gastrointestinal tract and peripheral tissues (Nakamura et al, 2008;Court et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

et al. 2013

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The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 59 region but alternative 39 ends namely UGT2B7_v5 (containing a novel terminal exon 6b) and _v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (K m ). Finally, coimmunoprecipitation experiments support a direct proteinprotein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.

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Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate

Cited by 41 publications

References 47 publications

Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis

Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

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