ROLE OF GLUTATHIONE AND METHYLATION IN THE BILIARY-EXCRETION OF SELENIUM - THE PARADOXICAL EFFECT OF SULFOBROMOPHTHALEIN

Biotransformation of selenite involves both reactions with GSH and met hylations. Therefore, the role of GSH, methylation, and the hepatobili ary GSH transporter was investigated in the biliary excretion of selen ium in rats injected with sodium [Se-75]selenite (1-10 mu mol/kg, i.v. ). Biliary output of selenium exhibited an apparent capacity limitatio n with an approximately 3 nmol/kg.min maximal rate and a dose-related decline in the fractional excretion. HPLC analysis of bile indicated a bsence of selenite and presence of selenodiglutathione (GS-Se-SG) and/ or its hydrolysis products as the major biliary selenite metabolites. Depletion of hepatic glutathione by D,L-buthionine-[S,R]-sulfoximine o r diethyl maleate decreased selenium excretion into bile by 60 and 80% , respectively. In contrast, inhibitors of methylation, i.e. periodate -oxidised adenosine or ethionine doubled the rate of biliary selenium excretion, While indocyanine green-an inhibitor of hepatobiliary GSH t ransport-failed to influence biliary selenium output, sulfobromophthal ein (BSP)-another inhibitor of this sort-dramatically enhanced it. Thi s effect was found to be a function of the dose of both selenite and B SP. The degree of BSP-induced enhancement of the selenium excretion ra te gradually increased with elevation of the selenite dose, approachin g 20-fold at 10 mu mol/kg selenite. In contrast, the stimulatory effec t of BSP on biliary selenium output was maximal at 50-100 mu mol/kg an d gradually lessened with elevation of the BSP dose above 100 mu mol/k g. In summary, this study revealed that the biliary excretion of selen ium depended on availability of hepatic GSH, probably for formation of GS-Se-SG, the putative cholephilic selenite metabolite. Methylation c ounteracted selenium excretion into bile and thus may contribute to th e apparent capacity limitation of biliary selenium excretion. Finally, selenium output into bile was insensitive to inhibitors of the hepato biliary GSH transporter, and was enhanced, paradoxically, by BSP sever al-fold. The mechanism of this unexpected effect is explored in the ad joining article. BIOCHEM PHARMACOL 56;10:1381-1389, 1998. (C) 1998 Els evier Science Inc.