Dubin-Johnson and Rotor syndromes: molecular basis and pathogenesis

The Dubin-Johnson syndrome, as well as the related conjugated hyperbilirubinemia conditions found in sheep and in rats, are most likely caused by a congenital impairment of an ATP-dependent transport system specific for a variety of multivalent organic anions, including bilirubin diglucuronide. Bilirubin is thus conjugated but inefficiently secreted into bile. The symptoms are mild, possibly due to the presence of residual transport activity in the membrane catalyzed by separate transport proteins. Corollary effects include, at least in rats, a reduction of bile acid-independent bile flow due to the inhibition of biliary GSH transport by accumulating substrates of the defective transporter. Dark discoloration of the liver is evident in humans and sheep but not (or to a lesser extent) in the albino rats. The discoloration is due to deposition of a pigment formed from products of amino acid catabolism that cannot be secreted into bile. The relationship of further secondary effects, such as a change in the pattern of excreted coproporphyrins, to the primary defect is less well defined. The identification of the canalicular transporter or transporters for organic anions and a molecular characterization of the defects are in progress.