Effect of arsenicals on biliary excretion of endogenous glutathione and xenobiotics with glutathione-dependent hepatobiliary transport

Sodium arsenite (25–100 μmol/kg, i.v.) and arsenate (75–300 μmol/kg, i.v.) injected into anaesthetized rats increased the biliary excretion of endogenous non-protein thiols (NPSH) in a dose-dependent fashion up to 24- and 31-fold, respectively. Simultaneously with NPSH, glutathione (GS) excretion was increased to a similar extent suggesting that the increment in biliary thiol output originated from enhanced hepatobiliary transport of GS. After administration of labelled arsenicals, biliary excretion of 74As and NPSH followed similar time-courses. Biliary excretion of 74As was more efficient after arsenite than arsenate administration corresponding to the greater potency of arsenite compared to arsenate to increase biliary output of NPSH. Coadministered sulfobromophthalein (BSP) inhibited the biliary excretion of 74As and prevented the arsenical-induced increase in biliary NPSH. Thus, hepatobiliary transport of arsenic apparently proceeds coordinately with that of GS. However, excretion of each molecule of arsenic compound generates transport of several molecules of GS. Though mercuric, methylmercuric, cadmium and zinc ions are thought to be excreted into bile as complexes with GS, the marked arsenical-induced increase in GS excretion only doubled the biliary excretion of inorganic mercury and hardly influenced the transport of other metals into bile. This finding suggests that arsenicals markedly enhance biliary excretion of GS with a free thiol group but barely or not at all that of GS with a thiol group blocked by a firmly bound metal ion. Both arsenicals diminished the biliary excretion of BSP-glutathione conjugate after BSP administration presumably because they impaired conjugation of BSP with GSH due to decreased GS availability. It is assumed that arsenite, and arsenate after reduction to arsenite, forms an unstable complex with GS that is efficiently transported into bile resulting in increased biliary output of GS. It is demonstrated that arsenite-induced perturbation of hepatobiliary disposition of endogenous GS differentially affects biliary excretion of xenobiotics with GS-dependent hepatobiliary transport.