Stimulation of biliary glutathione secretion by sulfonylureas

In isolated perfused rat livers, infusion of the sulfonylureas, glyburide (2.5 microM) and tolbutamide (0.5 mM), stimulated by 2-fold the rate of biliary glutathione secretion. This increase was mainly the result of an apparent increase in the rate of reduced glutathione release by the liver since oxidized glutathione levels in the bile remained unchanged. Sulfonylurea infusion into perfused livers did not alter the rate of glutathione release in the perfusate, indicating that sinusoidal release was not perturbed. N-Benzylimidazole (0.2 mM), an inhibitor of cytochrome P-450, blocked the tolbutamide-mediated increase in biliary release of glutathione. However, the cytochrome P-450 inhibitor did not alter the glyburide-induced increase in biliary glutathione secretion. Glyburide infusion into perfused livers also decreased tissue oxidized glutathione content without altering the total tissue levels of glutathione. The stimulation of biliary glutathione release by sulfonylureas is probably the result of excretion of labile conjugates of glutathione and sulfonylurea metabolites. Although the precise identity of these metabolites is presently unknown, formyltolbutamide and hydroxyglyburide formed during metabolism of tolbutamide and glyburide, respectively, may be the prime candidates for forming labile glutathione conjugates.