Cyanidin 3-glucoside Is a Selective Inhibitor of Hepatic Bilirubin Uptake

Background & Aims: One of the organ-specific functions of the liver is the excretion of bilirubin into the bile. Membrane transport of bilirubin from the blood to the liver is not only an orphan function, as there is no link to the protein/gene entities that carry it out, but also a poorly characterised function. The aim of this study was to investigate the pharmacology of bilirubin uptake in the liver of the female Wistar rat to improve basic knowledge in this neglected area of liver physiology.Methods: We treated isolated, perfused rat livers with repeated single-pass, albumin-free bilirubin boli. We monitored both bilirubin and bilirubin glucuronide in perfusion effluent with a biofluorometric assay. We tested the ability of nine molecules known to be substrates or inhibitors of sinusoidal membrane transporters to inhibit the hepatic uptake of bilirubin.Results: We found that cyanidin 3-glucoside and malvidin 3-glucoside are the only molecules that inhibit bilirubin uptake. These dietary anthocyanins resemble bromosulfophthalein (BSP), a substrate of several sinusoidal membrane transporters. The SLCO-specific substrates estradiol-17 beta-glucuronide, pravastatin, and taurocholate inhibited only bilirubin glucuronide uptake. Cyanidin 3-glucoside and taurocholate acted at physiological concentrations. The SLC22-specific substrates indomethacin and ketoprofen were inactive. We demonstrated the existence of a bilirubin glucuronide transporter that is inhibited by bilirubin, a fact reported only once in the literature.Conclusions: Data indicate that bilirubin and bilirubin glucuronide are transported into the liver via pharmacologically distinct membrane transport pathways. Some dietary anthocyanins may physiologically modulate the uptake of bilirubin into the liver.