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J Biol Chem, Vol. 274, Issue 16, 10852-10862, April 16, 1999
,
From the The liver is responsible for the clearance and
metabolism of unconjugated bilirubin, the hydrophobic end-product of
heme catabolism. Although several putative bilirubin transporters have
been described, it has been alternatively proposed that bilirubin
enters the hepatocyte by passive diffusion through the plasma membrane.
In order to elucidate the mechanism of bilirubin uptake, we measured
the rate of bilirubin transmembrane diffusion (flip-flop) using
stopped-flow fluorescence techniques. Unconjugated bilirubin rapidly
diffuses through model phosphatidylcholine vesicles, with a first-order rate constant of 5.3 s
Division of Digestive Diseases, University
of Cincinnati Medical Center, Cincinnati, Ohio 45267-0595, the
¶ Department of Medicine, Brigham and Women's Hospital, Boston,
Massachusetts 02115, and the
Division of Pediatric
Gastroenterology, Massachusetts General Hospital,
Boston, Massachusetts 02114
1 (t1/2 = 130 ms). The flip-flop rate is independent of membrane cholesterol
content, phospholipid acyl saturation, and lipid packing, consistent
with thermodynamic analyses demonstrating minimal steric constraint to
bilirubin transmembrane diffusion. The coincident decrease in pH of the
entrapped vesicle volume supports a mechanism whereby the bilirubin
molecule crosses the lipid bilayer as the uncharged diacid. Transport
of bilirubin by native rat hepatocyte membranes exhibits kinetics
comparable with that in model vesicles, suggesting that unconjugated
bilirubin crosses cellular membranes by passive diffusion through the
hydrophobic lipid core. In contrast, there is no demonstrable flip-flop
of bilirubin diglucuronide or bilirubin ditaurate in phospholipid vesicles, yet these compounds rapidly traverse isolated rat hepatocyte membranes, confirming the presence of a facilitated uptake system(s) for hydrophilic bilirubin conjugates.
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