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Unconjugated bilirubin (UCB), the principal mammalian bile pigment, is the end intravascular product of heme catabolism. Like many weakly polar, poorly soluble compounds, UCB is transported in blood tightly bound to albumin, with less than 0.01% of total bilirubin circulating in an unbound form (free bilirubin [Bf]). This fraction governs UCB tissue flux, and is responsible for its pathophysiological effects on cells and tissues.

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The transport mechanisms of different organic anions across the hepatocyte membrane have been the subject of extensive investigation over the last three decades. The primary reason for this interest is the crucial role played by the liver in the biotransformation of several endogenous and exogenous substances and their secretion via the biliary system. UCB is no exception since this endogenous organic anion is taken up rapidly and selectively by the liver and secreted into the bile after metabolic biotransformation (conjugation).

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The uptake of UCB across the basolateral membrane of the hepatocyte may be a carrier-mediated process based on experiments performed with different experimental models ranging from isolated basolateral plasma membrane–enriched vesicles to isolated and perfused liver. It is generally accepted that UCB enters the liver cells via a saturable, possibly carrier-mediated mechanism at low concentration (<40–50 nM) while its transport across the basolateral plasma membrane is passive and concentration dependent when the Bf concentration increases above certain levels (≈70 nM). Spontaneous diffusion accounts for the observation that UCB may enter any cell when its plasma concentration reaches a certain threshold. Evidence has accrued that the spontaneous transmembrane UCB diffusion is rapid and efficient, and that the overall transfer is mainly determined by the dissociation rate of UCB from albumin.

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Diffusion across the cell plasma membrane is particularly important to account the entry of UCB in cells other than the hepatocyte that has a unique mechanism for conjugating the pigment. As high concentrations of UCB in the cell are toxic, it is important to understand the mechanisms by which UCB diffused into the cell can be eliminated therefrom.

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In the 1990s, an extensive debate took place on the nature and the existence of UCB transporter(s) involved in the transmembrane passage of the pigment, particularly in the hepatocyte. At least four different putative transporters were suggested (bilirubin/BSP-binding protein [BBBP], organic anion–binding protein [OABP], bilitranslocase, and organic anion–transporting polypeptide [OATP])1 but the use of surrogate dyes instead of bilirubin limited the conclusive nature of these studies. More recently data have been provided indicating that one member of the OATP family, human SLC01B1 (OATP1B1), also known as SLC21A6, OATP2, OATPC, and LST-1, may mediate hepatic bilirubin transport.2 This conclusion was not confirmed in a subsequent study, however, leaving the issue of OATP1B1-mediated bilirubin membrane transport still unsettled. Data obtained in isolated liver cells, however, do indicate that UCB enters the cells in a saturable, carrier-mediated mechanism at low concentration. However, the molecular species involved in this function requires further investigation.3 The role of another putative transport protein in UCB uptake by the liver, SLC01B3 (OATP8), is not clear. The available studies indicate that when expressed in HEK293 cells, this carrier is able to transport at least monoglucuronosyl bilirubin.2,4 The carrier-mediated transport of UCB was also assessed in placenta with regard to the potential involvement of three members of the SLC21A family of carriers described at the level of the liver cell ...

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