Membrane Transporters for Bilirubin and Its Conjugates: A Systematic Review.

Jovana Čvorović,Sabina Passamonti

doi:10.3389/fphar.2017.00887

Abstract

Background: Bilirubin is a highly-hydrophobic tetrapyrrole which binds to plasma albumin. It is conjugated in the liver to glucuronic acid, and the water-soluble glucuronides are excreted in urine and bile. The membrane transporters of bilirubin diglucuronide are well-known. Still undefined are however the transporters performing the uptake of bilirubin from the blood into the liver, a process known to be fast and not rate-limited. The biological importance of this process may be appraised by considering that in normal adults 200–300 mg of bilirubin are produced daily, as a result of the physiologic turnover of hemoglobin and cellular cytochromes. Nevertheless, research in this field has yielded controversial and contradicting results. We have undertaken a systematic review of the literature, believing in its utility to improve the existing knowledge and promote further advancements.Methods: We have sourced the PubMed database until 30 June 2017 by applying 5 sequential searches. Screening and eligibility criteria were applied to retain research articles reporting results obtained by using bilirubin molecules in membrane transport assays in vitro or by assessing serum bilirubin levels in in vivo experiments.Results: We have identified 311 articles, retaining 44, reporting data on experimental models having 6 incremental increases of complexity (isolated proteins, membrane vesicles, cells, organ fragments, in vivo rodents, and human studies), demonstrating the function of 19 membrane transporters, encoded by either SLCO or ABC genes. Three other bilirubin transporters have no gene, though one, i.e., bilitranslocase, is annotated in the Transporter Classification Database.Conclusions: This is the first review that has systematically examined the membrane transporters for bilirubin and its conjugates. Paradoxically, the remarkable advancements in the field of membrane transport of bilirubin have pointed to the elusive mechanism(s) enabling bilirubin to diffuse into the liver as if no cellular boundary existed.

Highlights

Bilirubin (BR) is a tetrapyrrolic pigment found in plasma as an albumin-bound reversible complex (Jacobsen and Brodersen, 1983)
The article section “Results” reports experimental data about transport and distribution of bilirubin in compartments separated by biological membranes
Bilirubin was tested as inducer of the expression of membrane transporters, without experimental proof of change in bilirubin transport activity or distribution in compartments

Summary

Introduction

Bilirubin (BR) is a tetrapyrrolic pigment found in plasma as an albumin-bound reversible complex (Jacobsen and Brodersen, 1983). Considering sinusoidal uptake of BR, the liver has the capacity to take up as much as 50% of a BR load in a single pass (Stollman et al, 1983) by a process that shows substrate saturation and competitive inhibition by other organic anions, like indocyanine green and bromosulfophthalein (BSP) (Hunton et al, 1961; Scharschmidt et al, 1975; Bloomer and Zaccaria, 1976). This is evidence for a transporter-mediated process. We have undertaken a systematic review of the literature, believing in its utility to improve the existing knowledge and promote further advancements

Objectives

Methods

Results

Discussion

Conclusion