New insights in bilirubin metabolism and their clinical implications

Abstract

Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.

Keywords: Hyperbilirubinemia; Hereditary jaundice; UGT1A1; ABCC2; Organic anion transporting polypeptide 1B1; Organic anion transporting polypeptide 1B3

Core tip: Experiments with Oatp1a/1b-null mice and Oatp1a/1b; Abcc3 combination knockout mice plainly demonstrated that even under physiologic conditions a substantial portion of bilirubin glucuronides is not excreted directly into bile but is transported back to the blood by Abcc3. Oatp1a/1b activity accentuated in downstream (centrizonal) hepatocytes allows efficient reuptake of bilirubin conjugates, with a subsequent possibility being safely eliminated by excretion into bile. This and molecular findings in Rotor syndrome suggest that human transporters MRP3 and OATP1Bs form a sinusoidal liver-to-blood cycle which mediates shifting (hopping) of bilirubin and other substrates from periportal to centrizonal hepatocytes (References 18, 19, 22, 125).