Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy

Neumann, Ulf; Biermer, Michael; Eurich, Dennis; Neuhaus, P.; Berg, Thomas

doi:10.1016/j.jhep.2010.02.002

Cited by 78 publications

(65 citation statements)

References 6 publications

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“…With exception of OATP2B1, which showed no transport activity for this compound (Kullak-Ublick et al, 2001), OATP1B1-and OATP1B3-mediated DHEAS transport was also significantly inhibited by silibinin. These findings support a contribution of these transporters to hyperbilirubinemia observed during silibinin treatment (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013) and are in accordance with the observation that flavonoids, a class of natural products to which silibinin belongs, are able to inhibit OATP function (Roth et al, 2012). Under high-dose silibinin treatment regimens, plasma C max values of up to 30 mM (P.F., unpublished data) are observed in the range of the observed inhibitory concentrations of silibinin against OATPs and MRP2 ranging from 3 to 7 mM (OATP1B1: IC 50 = 3.28 mM; OATP1B3: K i = 5 mM; OATP2B1: K i = 3.64 mM; MRP2: IC 50 = 6.79 mM).…”

Section: Discussionsupporting

confidence: 83%

“…calculated from triplicate measurements. further increased between 1.2-and 6-fold during silibinin treatment, which has also been reported in other cases (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013). High interindividual variability is observed in serum bilirubin levels during silibinin treatment over the monitored period.…”

Section: Discussionsupporting

confidence: 81%

“…This study was motivated by the clinical observation that patients treated with high i.v. doses of silibinin often have elevated bilirubin levels (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013). Table 1 shows total serum bilirubin levels of 14 patients treated with high-dose i.v.…”

Section: Discussionmentioning

confidence: 99%

“…A positive effect of silibinin administration on hepatitis C was also observed in patients undergoing liver transplantation, in whom silibinin prevents reinfection after transplantation (Neumann et al, 2010;Beinhardt et al, 2011;Eurich et al, 2011;Rutter et al, 2011;Marino et al, 2013). Although administration of silibinin was generally well tolerated, a significant increase in serum bilirubin levels was reported in several studies (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013). Currently, the underlying mechanism of serum bilirubin elevation during silibinin treatment of HCV patients is unknown.…”

Section: Introductionmentioning

confidence: 91%

“…Promising outcomes have been reported after silibinin treatment of chronic hepatitis C nonresponders (Ferenci et al, 2008;Biermer and Berg, 2009;Rutter et al, 2011). A positive effect of silibinin administration on hepatitis C was also observed in patients undergoing liver transplantation, in whom silibinin prevents reinfection after transplantation (Neumann et al, 2010;Beinhardt et al, 2011;Eurich et al, 2011;Rutter et al, 2011;Marino et al, 2013). Although administration of silibinin was generally well tolerated, a significant increase in serum bilirubin levels was reported in several studies (Neumann et al, 2010;Beinhardt et al, 2011;Rutter et al, 2011;Marino et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

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Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

et al. 2013

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Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na + -taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17b-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinininduced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.

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