Gallbladder mucin as a pronucleating agent for cholesterol monohydrate crystals in bile. Mucin is a densely glycosylated macromolecule secreted by the gallbladder epithelium as the principal constituent of gallbladder mucus. Hypersecretion of gallbladder mucus occurs in response to a lithogenic diet in experimental animals, and mucus accumulates as a viscous gel within the gallbladder lumen before gallstone formation. In both animals and man, the initial stage of cholesterol gallstone formation, the nucleation of cholesterol monohydrate crystals, occurs within the mucus gel. Inhibition of mucus secretion with aspirin prevents gallstone formation in the cholesterol-fed prairie dog, indicating the importance of mucus in gallstone formation. Mucin contains domains that bind cholesterol and lecithin transported as vesicles in supersaturated bile. Furthermore, mucin accelerates the nucleation of cholesterol crystals in both supersaturated model and native biles. Binding of cholesterol-enriched vesicles to hydrophobic domains on the mucin protein core appears to be critical for the acceleration of cholesterol crystal nucleation by mucin. Further study of the structure and function of gallbladder mucin should help to elucidate the pathogenesis of cholesterol cholelithiasis. 