The gastrointestinal epithelium is continuously exposed to reactive oxygen metabolites that are generated within the lumen. In spite of this exposure, the healthy epithelium appears unaffected, suggesting efficient mechanisms for protection against these potentially cytotoxic oxidants. The objective of this study is to characterize the interaction between purified gastric mucin and hydroxyl radicals generated from the interaction between ferric iron and ascorbic acid. We found that both native and pronase-treated mucin effectively scavenged hydroxyl radical and that the scavenging properties were not significantly different. The effective concentration of mucin required for a 50% reduction in malondialdehyde production was approximately 10 mg/ml for both native and pronase-treated mucin. In addition, the iron-ascorbic system produced a dramatic decrease (greater than 50%) in the specific viscosity of mucin that was inhibited by catalase, deferoxamine, and mannitol. Superoxide dismutase had no effect. These data suggest that hydroxyl radicals derived from the iron-catalyzed decomposition of hydrogen peroxide are responsible for the depolymerization of native mucin. We propose that mucin may provide protection to the surface epithelium of the gastrointestinal tract by scavenging oxidants produced within the lumen; however, it does so at the expense of its viscoelastic properties.

A critical step in the formation of cholesterol gallstones is nucleation (i.e., the formation of cholesterol monohydrate crystals from supersaturated bile). The rate of nucleation of cholesterol depends upon a critical balance between pronucleating and antinucleating factors in bile. Mucin, a high molecular weight glycoprotein secreted by the gallbladder and biliary duct epithelium, is a pronucleating agent in experimental and human gallstone disease. Gallbladder mucin shares with other epithelial mucins the ability to bind lipids and bile pigment. The hydrophobic binding sites in the polypeptide core of mucin may provide a favorable environment for nucleation of cholesterol monohydrate from supersaturated bile. In nearly all animal models of cholelithiasis, mucin hypersecretion is prominent. The stimulus for gallbladder mucin hypersecretion appears to be a component of lithogenic bile. Prostaglandins regulate much release in gallbladder epithelium in uitro and probably in viuo. In the cholesterol-fed prairie dog, blockage of mucin release with aspirin inhibits gallstone formation. These findings suggest that inhibition of much release may prevent cholesterol stone formation during high-risk periods or after dissolution therapy with bile salts.The idea that gallbladder mucust secretion might contribute to gallstone formation is not a new one, having been formulated in the early writings of Galen, Paracelsus and Morgagni (1,2). In 1856, Meckel von Helmbach stated, "Two basic factors underlie the formation of every true gall or urinary stone; first the presence of an organic substance, mucus, in which there may be deposition of salts; second, a suitable urinary or gall fluid to serve as the mother liquor for these sediments" (3).In the last two decades, gallstone research has been focused sharply on the physical chemistry of bile; in particular, the contribution of biliary lipid abnormalities to cholelithiasis. Admirand and Small (4) identified the importance of cholesterol supersaturation in gallstone disease. It is now clear that supersaturation alone does not explain the formation of cholesterol gallstones, as many normal individuals without crystals or stones have

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