Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6

Bilirubin, the end product of heme catabolism, is taken up from the blood c irculation into the liver. This work identifies a high-affinity transport p rotein mediating the uptake of bilirubin and its conjugates into human hepa tocytes. Human embryonic kidney cells (HEK293) permanently expressing the r ecombinant organic anion-transporting polypeptide 2 (human OATP2, also know n as LST-1 or OATP-C; symbol SLC21A6) showed uptake of [H-3]monoglucuronosy l bilirubin, [H-3]bisglucuronosyl bilirubin, and [H-3]sulfobromophthalein w ith X, values of 0,10, 0,28, and 0.14,muM, respectively. High-affinity upta ke of unconjugated [H-3]bilirubin by OATP2 occurred in the presence of albu min and was not mediated by another basolateral hepatic uptake transporter, human OATP8 (symbol SLC21A8), OATP2 and OATP8 differed by their capacity t o extract substrates from albumin before transport. In comparison to the hi gh-affinity transport by OATP8, OATP8 transported [H-3]sulfobromophthalein and [H-3]monoglucuronosyl bilirubin with lower affinity, with K-m values of 3.3 and 0.5 muM. respectively. The organic anion indocyanine green potentl y inhibited transport mediated by OATP2, with a Ki value of 112 nM, but did not inhibit transport mediated by OATP8, Human OATP2 may play a key role i n the prevention of hyperbilirubinemia by facilitating the selective entry of unconjugated bilirubin and its glucuronate conjugates into human hepatoc ytes.