Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
Drug Metab Dispos. 2013 Aug;41(8):1522-8. doi: 10.1124/dmd.113.051037. Epub 2013 May 21.
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-17β-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 silibinin-induced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.
水飞蓟宾被报道是一种有前景的治疗丙型肝炎药物，可用于治疗对标准治疗无应答的患者。虽然给予水飞蓟宾是耐受良好的，但在高剂量静脉内水飞蓟宾治疗期间观察到血清胆红素水平升高。然而，到目前为止，水飞蓟宾诱导人类高胆红素血症的机制尚未确定。本研究的目的是研究水飞蓟宾对肝细胞摄取和有机阴离子外排转运系统的影响，以阐明水飞蓟宾诱导高胆红素血症的原因。因此，研究了水飞蓟宾对肝细胞摄取转运体有机阴离子转运多肽（OATPs）OATP1B1、OATP1B3 和 OATP2B1 以及 Na(+)-牛磺胆酸钠共转运蛋白（NTCP）和外排转运体多药耐药相关蛋白 2（MRP2）和胆汁盐输出泵（BSEP）的转运活性的影响。使用放射性标记的模型底物雌酮-3-硫酸盐和脱氢表雄酮硫酸盐用于 OATPs 和牛磺胆酸钠用于 NTCP，在稳定转染的中国仓鼠卵巢细胞中研究了水飞蓟宾对 OATPs 和 NTCP 功能的影响。使用表达这些转运体的 Sf21 或 Sf9 昆虫细胞分离的囊泡测量了水飞蓟宾与 MRP2 和 BSEP 的相互作用，使用雌二醇-17β-葡糖苷酸或牛磺胆酸钠作为底物。OATP1B1、OATP1B3 和 OATP2B1 被水飞蓟宾抑制，OATP1B1 被（一种）复杂机制抑制。也观察到对 MRP2 的抑制作用。相反，胆汁酸转运体 NTCP 和 BSEP 不受水飞蓟宾影响。我们得出结论，水飞蓟宾诱导的高胆红素血症可能是由于胆红素转运 OATPs 和外排转运体 MRP2 的抑制所致。
