ENHANCEMENT OF SELENIUM EXCRETION IN BILE BY SULFOBROMOPHTHALEIN - ELUCIDATION OF THE MECHANISM

This work was intended to explore the mechanism whereby sulfobromophth alein (BSP), an electrophilic and cholephilic organic acid, increases the biliary excretion of selenium in rats injected with sodium [Se-75] selenite. In such animals, neither BSP-glutathione conjugate nor dibro mosulfophthalein, nonelectrophilic congeners of BSP, enhanced the hepa tobiliary transport of selenium, suggesting that reaction of nucleophi lic selenite metabolites formed in vivo with the injected BSP may be i nvolved. Indeed, HPLC analysis of bile from rats receiving [Se-75]sele nite and BSP revealed two peaks (X and Y) that were simultaneously det ected both by absorbance as BSP metabolites and by radioactivity as [S e-75] metabolites, indicating that these represent selenium-containing BSP metabolites. Pretreatment of rats with inhibitors of selenium met hylation, such as periodate-oxidized adenosine (PAD) and ethionine, dr astically diminished the size of peak X, while increasing (PAD) or not influencing (ethionine) the size of peak Y. This finding indicates th at production of metabolite X, but not Y, is dependent on formation of methylated selenium metabolites. A compound chromatographically indis tinguishable from that in peak X was formed in vitro during incubation of BSP with methylselenol, suggesting that biliary metabolite X is id entical to the reaction product of BSP and selenite-derived methylsele nol. Incubation of BSP with selenite in the presence of a thiol, namel y glutathione,cysteine or N-acetylcysteine (which convert selenite int o nucleophilic products, i.e. the respective selenopersulfides and hyd rogen selenide) resulted in product(s) chromatographically identical t o the biliary selenium-containing BSP metabolite(s) of peak Y, irrespe ctive of the nature of the thiol used. Thus, biliary metabolite(s) Y m ay be reaction products of BSP and hydrogen selenide. Finally, BSP sig nificantly diminished exhalation of dimethyl selenide in selenite-inje cted rats, purportedly because it reacted with precursors of dimethyl selenide, that include hydrogen selenide and methylselenol. In summary , BSP increases biliary excretion of selenium in rats receiving seleni te because it forms selenium-containing BSP metabolites that are readi ly transported into bile. It is suggested that the in vivo reaction of nucleophilic selenite metabolites with electrophilic compounds may in fluence the fate of selenium and may contribute to some of the effects of this essential and anticarcinogenic metalloid. BIOCHEM PHARMACOL 5 6;10:1391-1402, 1998. (C) 1998 Elsevier Science Inc.