Bilirubin throughput in hepatocytes

Schematic representation of the steps involved in bilirubin (B) throughput in hepatocytes: transport to the liver (primarily as albumin-bound bilirubin), uptake at the sinusoidal membrane, intracellular binding, conjugation (glucuronidation), and canalicular excretion. Sinusoidal bilirubin uptake requires inorganic anions such as chloride and is thought to be mediated by carrier proteins. Within the hepatocyte, bilirubin binds to glutathione S-transferases (GSTs). GST-binding reduces the efflux of the internalized bilirubin, thereby increasing the net uptake. GSTs also bind bilirubin glucuronides (BG) prior to excretion. Bilirubin also enters hepatocytes by passive diffusion. Glucuronidation of bilirubin is mediated by a family of enzymes, termed uridine diphosphoglucuronosyltransferase (UGT), the most important of which is bilirubin-UGT-1 (UGT1A1). Conjugated bilirubin is secreted actively across the bile canalicular membrane of the hepatocyte against a concentration gradient that may reach 1:1000. The canalicular multidrug resistance protein 2 (MRP2) appears to be the most important for the canalicular secretion of bilirubin. A portion of the conjugated bilirubin is transported into the sinusoidal blood via the ATP hydrolysis-couple pump, ABCC3, to undergo reuptake via OATP1B1 and OATP1B3 by hepatocytes downstream to the sinusoidal blood flow.