Melatonin Prevents Pigment Gallstone Formation Induced by Bile Duct Ligation in Guinea Pigs

Abstract

Free radical-mediated oxidative stress has been implicated in the genesis of gallstone in vitro. This study was designed to examine the oxidative stress changes during pigment gallstone formation and to investigate whether melatonin (MLT) could act as a chemopreventive agent for cholelithiasis in a guinea pig model. The common bile duct of guinea pigs was ligated with or without MLT pretreatment. Animals were studied on day 7, 9, 12, and 14 after surgery. Stone and/or sludge developed in ligated guinea pigs without MLT. Fourier transform infrared spectra of the sludge showed the presence of calcium bilirubinate, whose peak height per milligram of sludge gradually increased with time after ligation. Total antioxidant activity (TAA) in bile of guinea pigs at day 14 after ligation reduced to one third of the level in sham-operated controls (P < .001). In addition, the bile of ligated guinea pigs had increased pH (P < .001), bile salts (P < .01), and malondialdehyde (MDA) (P < .05), compared to sham controls. Pretreatment of guinea pigs with MLT at a dose of 1,000 g/kg significantly decreased the incidence of pigment gallstone formation at day 14 after ligation, as compared to no pretreatment (0/7 vs. 8/10). MLT also reverted the ligation-induced changes in biliary bile salts, pH, MDA, and TAA to control levels. These in vivo findings support a causative role of oxidative stress in the bile duct ligation-induced pigment gallstone formation. Antioxidants may prove useful in preventing pigment gallstone formation in humans. (HEPATOLOGY 2000;32: 455-460.)Oxidative stress has been implicated in the pathogenesis and pathophysiology of more than 100 disease states. 1 Only a few studies have implicated oxidative stress in pigment gallstone. Hydroxyl radical was reported to stimulate a rapid release of glycoprotein from gallbladder epithelium in organ culture 2 and to be a promotor of cholesterol crystallization in model bile. 3 An in vitro experiment showed that an oxygen-free radical oxidized unconjugated bilirubin and led to the formation of a brown-black precipitation. 4 The presence of an oxygen-free radical has been reported in fresh pigment gallstone. 5 Moreover, increased F2-isoprostanes and 4-hydroxynonenal, products of lipid peroxidation, were observed in the bile of stone patients. 6 However, the role of oxidative stress in pigment gallstone formation is not fully understood.Gallbladder stasis resulting from mechanical obstruction is an important antecedent to the development of pigment gallstones and sludge. Changes in biliary content may facilitate the precipitation of calcium salts of bilirubinate or fatty acid and lead to the stone formation. Animal studies on bile duct ligation showed the effects of ligation on the increase of gallbladder mucins content, 7 liver mitochondrial lipid peroxidation, 8,9 and serum malondialdehyde (MDA), 9 and the decrease of liver vitamin E concentration and glutathione reductase activity. 9,10 Yet, no study has assessed the oxidative stress in bile during the course of sludge an...

Effects of Melatonin on Gallbladder Neuromuscular Function in Acute Cholecystitis

“…In addition to liver and hepatic damage, free radical accumulation associated with bile duct ligation has been implicated in the genesis of gallstone (Eder et al, 1996). In this regard, antioxidant treatment with melatonin not only reversed the increased oxidative stress but also prevented gallstone formation (Shiesh et al, 2000). In our preparation, either prophylactic or therapeutic melatonin treatments were effective in reducing MDA levels and in increasing the endogenous antioxidant defense…”

“…Recent evidence has shown that melatonin has protective effects on liver and hepatic injury after extrahepatic bile duct ligation in rats (Shiesh et al, 2000;Esrefoglu et al, 2005;Ohta et al, 2005). In addition to liver and hepatic damage, free radical accumulation associated with bile duct ligation has been implicated in the genesis of gallstone (Eder et al, 1996).…”

Can pigment gallstones be induced by biliary stricture and prevented by medicine in Guinea pigs

“…A 5-gauge dull needle (0.5 mm in diameter) was placed beside CBD and tied together with 1-0 suture. After withdrawing the needle, incomplete stricture of CBD was achieved [12] . Abdominal wall was closed.…”

“…It was indicated that the animal model of incomplete stricture of CBD was successful [12] . It is verified that incomplete stricture of CBD could induce pigment gallstone formation [23] .…”

Mechanism of Gallstones Formation in Women During Menopause (EPR Study)

“…This concentration, however, is sufficient for the oxidation of bilirubin (Eder, Miquel, Jongst, Paumgartner & von Ritter, 1996) in oxidative stress conditions, promoted by different endogenous (alterations of hormonal metabolism, infections) and exogenous (stress factors, sun bathing, light exposure) factors. Free-radical oxidation is involved in the pathogenesis of many pathological processes (Halliwell, Gutterigge & Cross, 1992), however, only a limited number of studies have been devoted to understand the role of oxidative processes in gallstones formation (Shiesh, Chen, Lin, Liu & Tsao 2000;Lightner et al, 1984). As a result of testing blood redox parameters of menopausal women with gallstone disease reduced activity of blood antioxidant ceruloplazmin/F 3+ -transferrin system and increased content of prooxidantsMn 2+ -ions were revealed.…”