Two Distinct Mechanisms for Bilirubin Glucuronide Transport by Rat Bile Canalicular Membrane Vesicles

Bilirubin is conjugated with glucuronic acid in hepatocytes and subsequently secreted in bile. The major conjugate is bilirubin diglucuronide. Using sealed vesicles which are primarily derived from the canalicular (CMV) and sinusoidal (SMV) membrane vesicle domains ofthe plasma membrane ofhepatocytes, we demonstrated that bilirubin glucuronides are transported byCMV by both ATP- and membrane potential-dependent transport systems. InCMV from normal rats, these processes are additive. In CMV from TR- rats, which have an autosomal recessively inherited defect in biliary secretion of nonbile acid organic anions, ATP-dependent transport ofbilirubin diglucuronide was absent whereas the membrane potential driven system was retained. Other canalicular ATP-dependent transport systems, which were previously described for organic cations and bile acids, are functionally retained in TR- rats. Our study indicates that bilirubin glucuronides are primarily secreted into the bile canaliculus by an ATP-dependent mechanism which is defective in an animal model ofthehuman DubinJohnson syndrome. (J. Clin. Invest. 1992.90:2130-2135.) Key words: ATP-dependent transport * bilirubin glucuronides* canalicular transport * inheritable jaundice (Dubin-Johnson syn