Mucin hypersecretion in the gallbladder is thought to be a key factor in the nucleation of cholesterol gallstones. In this study, we evaluated the effect of several oxygen radical-generating systems on glycoprotein release from guinea pig gallbladder explants. Hydroxyl radicals (OH.) released by hypoxanthine-xanthine oxidase or FeCl3-ascorbate caused a significant increase in glycoprotein secretion from gallbladder explants pre-incubated with [3H] glucosamine. Human neutrophils activated with f-Met-Leu-Phe, a chemotactic peptide, released oxygen radicals that also stimulated gallbladder glycoprotein release. The mechanism of this effect is most probably related to perturbation of lipid membrane structure by the oxygen radicals with subsequent activation of glycoprotein release.