Gallstones: Prevention



Cholesterol gallstone formation in man and potential treatments of the gallbladder motility defect.

Dept. of Gastroenterology, University Hospital Utrecht, The Netherlands.

Cholelithiasis affects 10-15% of the adult population in Western society, and about 75% of gallstones are of cholesterol type. Hepatic hypersecretion of cholesterol with the formation of instable cholesterol-rich vesicles in bile, an imbalance between nucleation-inhibiting and nucleation-promoting proteins with further aggregation of cholesterol crystals in a gallbladder with a motility defect (stasis), all play a role in the pathogenesis of cholesterol gallstones. Experimental animal models suggest that gallstone formation can be prevented by improving gallbladder emptying. Thus, a better understanding of the causes underlying the impaired gallbladder motor function in patients with gallstones might lead to the selection of therapeutic approaches for those individuals who are at increased risk for the formation or recurrence of gallstones. The present article focuses on current concepts and theories on the pathogenesis of cholesterol gallstones with emphasis on the gallbladder motility defect. Several treatment strategies for the correction of gallbladder hypomotility are also discussed.




Aliment Pharmacol Ther. 2000 May;14 Suppl 2:39-47.Click here to read Links

Review: pathogenesis of gallstones.

Gastroenterology Unit, Guy's, King's & St Thomas' School of Medicine, London, UK. h.dowling@umds.ac.uk

The aim of this article is to review selected aspects of the pathogenesis of cholesterol-rich, gall-bladder stones (GBS)--with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall-bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development. In biliary cholesterol secretion, transport and saturation, recent developments include evidence in humans and animals, that bile lipid secretion is under genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a 'flippase' transporting phospholipids from the inner to the outer hemi-leaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that have 'lith genes' are fed a lithogenic diet, they become susceptible to high rates of GBS formation. The precipitation/nucleation of cholesterol microcrystals from supersaturated bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original 'nucleation time' to measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addition to classical Rhomboid-shape monohydrate crystals, cholesterol can also crystallize, transiently, as needle-, spiral- and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined. There are many situations where GB stasis in humans is associated with an increased risk of gallstone formation--including iatrogenic stone formation in acromegalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have 'bad' bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal mulceation times and a two-fold increase in the percentage DCA in bile. This increase in the proportion of DCA seems to be due to OT-induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (III) the DCA input or 'synthesis' rate. Furthermore, the intestinal prokinetic, cisapride, counters the adverse effects of OT on intestinal transit, and 'normalizes' the percentage of DCA in serum/bile. Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic gram-positive anaerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values, than stone-free controls. Together, these changes lead to increased DCA formation, solubilization and absorption, Thus, in addition to the 'lithogenic liver' and 'guilty gall-bladder' one must now add the 'indolent intestine' to the list of culprits in cholesterol gallstone formation.



Liver Int. 2008 Aug;28(7):935-47.Click here to read Links
Comment in:
Liver Int. 2008 Aug;28(7):906-7.

Ezetimibe prevents cholesterol gallstone formation in mice.

Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

BACKGROUND: Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption. AIMS: To test whether EZET can prevent gallstone formation in mice. METHODS/RESULTS: Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P<0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P<0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman-Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans. CONCLUSIONS: In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.




Gastroenterology. 2008 Jun;134(7):2101-10. Epub 2008 Mar 10.Click here to read Links

Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones.

Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

BACKGROUND & AIMS: Cholesterol cholelithiasis is one of the most prevalent and most costly digestive diseases in developed countries and its incidence has increased markedly in Asian countries owing to the adoption of Western-type dietary habits. Because animal experiments showed that high efficiency of intestinal cholesterol absorption contributes to gallstone formation, we explored whether the potent cholesterol absorption inhibitor ezetimibe could prevent gallstones and promote gallstone dissolution in mice and reduce biliary cholesterol content in human beings. METHODS: Male gallstone-susceptible C57L mice were fed a lithogenic diet and concomitantly administered with ezetimibe at 0, 0.8, 4, or 8 mg/kg/day for 8 or 12 weeks. Gallbladder biles and gallstones were examined by microscopy. Gallbladder emptying in response to cholecystokinin octapeptide was measured gravimetrically. Biliary lipid outputs were analyzed by physical-chemical methods. Cholesterol absorption efficiency was determined by fecal dual-isotope ratio and mass balance methods. Lipid changes in gallbladder biles of gallstone patients vs overweight subjects without gallstones were examined before (day 0) and at 30 days after ezetimibe treatment (20 mg/day). RESULTS: Ezetimibe prevented gallstones by effectively reducing intestinal cholesterol absorption and biliary cholesterol secretion, and protected gallbladder motility function by desaturating bile in mice. Treatment with ezetimibe promoted the dissolution of gallstones by forming an abundance of unsaturated micelles. Furthermore, ezetimibe significantly reduced biliary cholesterol saturation and retarded cholesterol crystallization in biles of patients with gallstones. CONCLUSIONS: Ezetimibe is a novel approach to reduce biliary cholesterol content and a promising strategy for preventing or treating cholesterol gallstones by inhibiting intestinal cholesterol absorption.







Hepatology. 1992 Oct;16(4):960-7.Links

Dietary N-3 polyunsaturated fatty acids decrease biliary cholesterol saturation in gallstone disease.

Department of Medicine II, Klinikum Grosshadern, University of Munich, Germany.

Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p less than 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p less than 0.001) and arachidonic acids (p less than 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p less than 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 +/- 0.44 to 1.24 +/- 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile.






Cas Lek Cesk. 2007;146(1):24-34.Links

[Effect of hypolipidemic treatment on the composition of bile and the risk or cholesterol gallstone disease]

[Article in Czech]

IV interní klinika 1. LF UK a VFN, Praha. azak@vfn.cz

Obesity, diabetes mellitus type 2 and dyslipidemia, characterized by hypertriglyceridemia and low HDL-cholesterol levels, are risk factors for cholesterol gallstone disease. The common denominator of above-mentioned states is insulin resistance. Hypolipidemic treatment significantly influences not only the biliary lipid composition, but also other etiopathogenetic mechanisms of the disease. Three principal defects are involved in gallstone formation - cholesterol supersaturation, accelerated nucleation, and gallbladder dysmotility. The degree of cholesterol saturation in gallbladder bile is the most important predictor of cholesterol crystal formation. Cholesterol, lecithin and bile acids are the major components in bile. According to the molar ratios of the three main components, simple or mixed micelles, unstable unilamellar or multilamellar vesicles are formed in the bile. The cholesterol supersaturation of the gallbladder bile and cholesterol crystal formation from the unstable multilamellar vesicles initiates the onset of cholesterol cholelithiasis. The pool of unesterified cholesterol is the source for VLDL synthesis; together with HDL-cholesterol, it is also the source for cholesterol secretion into the bile. The main metabolic products of cholesterol degradation are bile acids, which are synthesized predominantly from LDL-cholesterol. The rate of the production of primary bile acids is principally regulated by cholesterol 7alpha-hydroxylase (CYP7A 1). The treatment of dyslipidemia with niacin and resins does not influence the saturation of bile with cholesterol or the incidence of cholelithiasis. The effects of ezetimibe in human patients with the respect of cholesterol cholelithiasis have not been published. The fibrate treatment is associated with increased cholesterol saturation of bile due to inhibition of CYP7A1 activity, enhanced flux of cholesterol via HDL and increased secretion of cholesterol into bile. The clinical studies describe cholesterol supersaturation in bile and increased frequency of cholelithiasis as well. The administration of pravastatin and simvastatin led to reduced cholesterol saturation indexes. The patients with endogenous hypertriglyceridemia and low HDL-cholesterol being administered with polyunsaturated fatty acids of n-3 family had decreased cholesterol concentration in bile. Other authors described beneficial effect of fish oil on the biliary cholesterol nucleation time, improvement of gallbladder sensitivity to cholecystokinin and the prevention of cholesterol gallstone formations caused by rapid weight loss.






Surgery. 2007 Aug;142(2):228-33.Click here to read Links

Ezetimibe ameliorates cholecystosteatosis.

Department of Surgery, Indiana University School of Medicine, Indianapolis, Ind, USA.

BACKGROUND: Cholecystosteatosis is the accumulation of gallbladder wall fats leading to decreased gallbladder emptying. Ezetimibe inhibits intestinal fat absorption and prevents murine gallstone formation. However, the influence of ezetimibe on gallbladder emptying and cholecystosteatosis has not been studied. Therefore, we tested the hypothesis that ezetimibe would improve gallbladder motility by preventing the buildup of fats in the gallbladder wall. METHODS: Forty lean female mice were fed either a control diet or a lithogenic diet for 6 weeks. Half of the mice on each diet received ezetimibe. At 11 weeks of age, all mice were fasted overnight and underwent gallbladder ultrasonography to determine ejection fraction. One week later, the mice were fasted and underwent cholecystectomy. Bile was examined for cholesterol crystals. The gallbladders were snap-frozen for lipid analysis. RESULTS: The lithogenic diet significantly (P < 0.05) increased serum cholesterol, biliary crystals, gallbladder wall cholesterol and cholesterol/phospholipid ratio, and decreased gallbladder ejection fraction. All of these abnormalities were reversed (P < 0.05) by the addition of ezetimibe to the diet. CONCLUSIONS: These data suggest that ezetimibe lowers serum cholesterol, prevents biliary crystals, and normalizes gallbladder wall fat and function. We conclude that ezetimibe ameliorates cholecystosteatosis and may be an effective agent for gallstone prevention.






Atherosclerosis. 2008 May;198(1):77-84. Epub 2007 Dec 3.Click here to read Links

Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice.

Department of Biology, Massachusetts Institute of Technology, Building 68-483, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

SR-BI/apoE double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including hypercholesterolemia, occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, cardiac dysfunction and premature death. Ezetimibe is a FDA-approved, intestinal cholesterol absorption inhibitor that lowers plasma LDL cholesterol in humans and animals and inhibits aortic root atherosclerosis in apoE KO mice, but has not been proven to reduce CHD. Three-week-ezetimibe treatment of dKO mice (0.005% (w/w) in standard chow administered from weaning) resulted in a 35% decrease in cholesterol in IDL/LDL-size lipoproteins, but not in VLDL- and HDL-size lipoproteins. Ezetimibe treatment significantly reduced aortic root (57%) and coronary arterial (68%) atherosclerosis, cardiomegaly (24%) and cardiac fibrosis (57%), and prolonged the lives of the mice (27%). This represents the first demonstration of beneficial effects of ezetimibe treatment on CHD. The dKO mice were similarly treated with SC-435 (0.01% (w/w)), an apical sodium codependent bile acid transporter (ASBT) inhibitor, that blocks intestinal absorption of bile acids, lowers plasma cholesterol in animals, and reduces aortic root atherosclerosis in apoE KO mice. The effects of SC-435 treatment were similar to those of ezetimibe: 37% decrease in ILD/LDL-size lipoprotein cholesterol and 57% prolongation in median lifespan. Thus, inhibition of intestinal absorption of either cholesterol (ezetimibe) or bile acids (SC-435) significantly reduced plasma IDL/LDL-size lipoprotein cholesterol levels and improved survival of SR-BI/apoE dKO mice. The SR-BI/apoE dKO murine model of atherosclerotic occlusive, arterial CHD appears to provide a useful system to evaluate compounds that modulate cholesterol homeostasis and atherosclerosis.




Hepatology. 2000 Sep;32(3):455-60.Click here to read Links
Comment in:
Hepatology. 2000 Sep;32(3):670-1.

Melatonin prevents pigment gallstone formation induced by bile duct ligation in guinea pigs.

Department of Medical Technology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China. hsieh@mail.ncku.edu.tw

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 microg/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.




J Physiol Pharmacol. 2007 Sep;58(3):381-405.Click here to read Links

Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT).

Department of Physiology, Jagiellonian University Medical College, Cracow, Poland. mpkontur@cyf-kr.edu.pl

Melatonin (MT), an indole formed enzymatically from L-trytophan (Trp), was first discovered in the bovine pineal gland in 1958 by Lerner et al. Melatonin is the most versatile and ubiquitous hormonal molecule produced not only in the pineal gland but also in various other tissues of invertebrates and vertebrates, particularly in the gastrointestinal tract (GIT). This review focuses on the localization, production, metabolism and the functions of MT in GIT and the duodenal unit (liver, biliary routes and pancreas), where multi-step biosynthetic pathways of this indole, similar to those in pinealocytes, have been identified. These biosynthetic steps of MT, including two major rate limiting enzymes; arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT), transforming L-tryptophan (Trp), originally identified in pinealocytes, have been also detected in entero-endocrine (EE) cells of GIT, where this indole appears to act in endocrine, paracrine and/or luminal pathway directly or through G-protein coupled MT receptors. Studies of the distribution of MT in GIT mucosa showed that this indole is generated in GIT in much larger amounts than it is produced in the pineal gland. Melatonin acts in GIT, partly locally in paracrine fashion and is partly released into portal circulation, to be taken up by the liver. It is then metabolized and excreted with the bile to small bowel and finally returns to liver through entero-hepatic circulation. The production of MT by the pineal gland shows circadian rhythm with high night-time surge, especially at younger age, followed by the fall during the day-light time. As a highly lipophylic substance, MT reaches all body cells within minutes, thus, serving as a convenient circadian timing signal. Following pinealectomy, the light/dark cycle of plasma MT levels disappears, while its day-time blood concentration is maintained mainly due to its release from the GIT. According to our experience, after oral application of Trp, the plasma MT increases in dose-dependent manner both in intact and pinealectomized animals and humans, indicating that GIT but not the pineal gland is a source of this indole. In GIT MT exhibits a wide spectrum of activities such as circadian entrainment, antioxidant and free radicals scavenging activity, Melatonin (MT), an indole formed enzymatically from L-trytophan (Trp), was first discovered in the bovine pineal gland in 1958 by Lerner et al. Melatonin is the most versatile and ubiquitous hormonal molecule produced not only in the pineal gland but also in various other tissues of invertebrates and vertebrates, particularly in the gastrointestinal tract (GIT). This review focuses on the localization, production, metabolism and the functions of MT in GIT and the duodenal unit (liver, biliary routes and pancreas), where multi-step biosynthetic pathways of this indole, similar to those in pinealocytes, have been identified. These biosynthetic steps of MT, including two major rate limiting enzymes; arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT), transforming L-tryptophan (Trp), originally identified in pinealocytes, have been also detected in entero-endocrine (EE) cells of GIT, where this indole appears to act in endocrine, paracrine and/or luminal pathway directly or through G-protein coupled MT receptors. Studies of the distribution of MT in GIT mucosa showed that this indole is generated in GIT in much larger amounts than it is produced in the pineal gland. Melatonin acts in GIT, partly locally in paracrine fashion and is partly released into portal circulation, to be taken up by the liver. It is then metabolized and excreted with the bile to small bowel and finally returns to liver through entero-hepatic circulation. The production of MT by the pineal gland shows circadian rhythm with high night-time surge, especially at younger age, followed by the fall during the day-light time. As a highly lipophylic substance, MT reaches all body cells within minutes, thus, serving as a convenient circadian timing signal. Following pinealectomy, the light/dark cycle of plasma MT levels disappears, while its day-time blood concentration is maintained mainly due to its release from the GIT. According to our experience, after oral application of Trp, the plasma MT increases in dose-dependent manner both in intact and pinealectomized animals and humans, indicating that GIT but not the pineal gland is a source of this indole. In GIT MT exhibits a wide spectrum of activities such as circadian entrainment, antioxidant and free radicals scavenging activity, cytoprotective, anti-inflammatory and healing efficacy of various GIT lesions such as esophagitis, gastritis, peptic ulcer, pancreatitis and colitis. This review concentrates on the generation and pathophysiological implication of MT in GIT and related organs.




J Physiol Pharmacol. 2008 Aug;59 Suppl 2:33-51.Click here to read Links

Thirty four years since the discovery of gastrointestinal melatonin.

Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada. gbubenik@uoguelph.ca

After the discovery of melatonin in the pineal gland by Lerner and co-workers in 1958, melatonin was also detected in the retina and the human appendix. Later, melatonin was confirmed immunohistologically in all segments of the gastrointestinal tract (GIT), in the guts of bovine embryos and in the GIT of low vertebrates. Melatonin was also confirmed in the pancreas and the hepatobiliary system. Melatonin is produced in the enteroendocrine cells of the GIT mucosa. The concentrations of melatonin in the GIT are 10-100x higher than in the plasma and the total amount of melatonin in the GIT is around 400x higher than the amount of melatonin in the pineal gland. Similar to pineal melatonin, GIT melatonin is a multifunctional compound which exhibits some general as well as some specific effects, depending on the organ and the location of GIT tissue. In the GIT, melatonin exhibits endocrine, paracrine, autocrine and luminal actions. Generally, the episodic secretion of melatonin from the GIT is related to the intake and digestion of food and to the prevention of tissue damage caused by hydrochloric acid and digestive enzymes. Some actions, such as the scavenging of hydroxyl free radicals, immunoenhancement and antioxidant effects are of general nature, whereas others, such as an increase of mucosal blood flow, the reduction of peristalsis and the regulation of fecal water content, are specific to the tubular GIT. Generally, melatonin actions oppose those of serotonin. Laboratory and clinical studies indicate that the utilization of melatonin can prevent or treat pathological conditions such as esophageal and gastric ulcers, pancreatitis, colitis, irritable bowel disease, and colon cancer.




J Pineal Res. 2004 Nov;37(4):267-75.Click here to read Links

Melatonin protects against pancreaticobiliary inflammation and associated remote organ injury in rats: role of neutrophils.

Department of General Surgery, Marmara University School of Medicine, Istanbul, Turkey.

Although the role of oxidative stress in acute pancreatitis (AP) has been studied in several animal models, little data are available regarding AP induced by pancreatic duct obstruction. We characterized the protective effects of melatonin on pancreaticobiliary inflammation and associated remote organ injury. In Sprague-Dawley rats, either the common pancreaticobiliary duct (PBDL; n = 28) or bile duct (BDL; n = 28) was ligated or a sham operation was applied (n = 14). Either melatonin (10 mg/kg) or vehicle (saline; 1 mL/kg) was administered intraperitoneally (i.p.) immediately before the surgery and twice a day until the rats were decapitated at 6 or 72 h. The pancreas, liver, kidneys and lungs were removed and tissue samples were stored for the determination of malondialdehyde (MDA) and glutathione (GSH) levels and myelopreoxidase activity. The results demonstrate that pathogenesis of acute obstructive pancreatitis involves not only the oxidative damage of the pancreatic and hepatic tissues, as assessed by increased MDA and reduced GSH levels, but the lungs and kidneys are also challenged by oxidant injury. Similarly, hepatic oxidative injury caused by cholestasis was also accompanied by pulmonary, renal and even pancreatic damage. The biochemical findings were also verified histologically. Melatonin, probably because of its free-radical scavenging and antioxidant activity, which involves an inhibitory effect on tissue neutrophil infiltration, protected all the affected tissues.



World J Gastroenterol. 2005 Apr 7;11(13):1951-6.Click here to read Links

Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats.

Department of Histology and Embryology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey. drmukaddes@hotmail.com

AIM: To investigate the role of oxidative injury and the effect of exogenous melatonin administration on liver damage induced by bile duct ligation (BDL), and second, to evaluate the role of nitric oxide (NO), a free oxygen radical, in oxidative injury. METHODS: Thirty-two Sprague-Dawley rats were assigned to four groups: sham operation (SO), BDL, BDL+melatonin, and BDL+vehicle. Cholestasis was achieved by double ligature of the common bile duct. Melatonin was injected intraperitoneally 500 microg/(kg.d) for 8 d. Hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA), and reduced GSH. Total nitrite (NOX) concentrations were determined in hepatic homogenates. Histopathological examination was performed using a histological scoring system. RESULTS: The histopathological changes including portal inflammation, necrosis, apoptosis, focal inflammation and fibrosis were severe in the BDL and BDL+vehicle groups. There were numerous large areas of coagulation necrosis. Histological Activity Index scores of these groups were significantly higher than that of the SO group. Treatment with melatonin reduced these alterations significantly. The degree of necro-inflammation and fibrosis showed significant difference between the BDL and BDL+melatonin groups. BDL was accompanied by a significant increase in MDA and NOX, and a significant decrease in GSH levels. Mean+/-SE values of MDA, GSH and NOX levels of SO group were 147.47+/-6.69, 0.88+/-0.33 micromol/g and 180.70+/-6.58 nm/g, respectively. The values of BDL group were 200.14+/-21.30, 0.65+/-0.02 micromol/g, and 400.46+/-48.89 nm/g, respectively, whereas the values of BDL+melatonin group were 115.93+/-6.8, 0.74+/-0.02 micromol/g, and 290.38+/-32.32 nm/g, respectively. Melatonin treatment was associated with a significant recovery of MDA, GSH and NOX levels. CONCLUSION: We have concluded that oxidative stress is associated with the pathogenesis of cholestatic liver damage and NO contributes to oxidative damage. Melatonin, even at low dose, is an efficient agent in reducing negative parameters of cholestasis.



J Pineal Res. 2008 Apr;44(3):250-60.Click here to read Links

Protective effect of melatonin on Ca2+ homeostasis and contractility in acute cholecystitis.

Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain.

Impaired Ca2+ homeostasis and smooth muscle contractility co-exist in acute cholecystitis (AC) leading to gallbladder dysfunction. There is no pharmacological treatment for this pathological condition. Our aim was to evaluate the effects of melatonin treatment on Ca2+ signaling pathways and contractility altered by cholecystitis. [Ca2+]i was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and isometric tension was recorded from gallbladder muscle strips. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined by spectrophotometry and cycloxygenase-2 (COX-2) expression was quantified by western blot. Melatonin was tested in two experimental groups, one of which underwent common bile duct ligation for 2 days and another that was later de-ligated for 2 days. Inflammation-induced impairment of Ca2+ responses to cholecystokinin and caffeine were recovered by melatonin treatment (30 mg/kg). This treatment also ameliorated the detrimental effects of AC on Ca2+ influx through both L-type and capacitative Ca2+ channels, and it was effective in preserving the pharmacological phenotype of these channels. Despite its effects on Ca2+ homeostasis, melatonin did not improve contractility. After de-ligation, Ca2+ influx and contractility were still impaired, but both were recovered by melatonin. These effects of melatonin were associated to a reduction of MDA levels, an increase in GSH content and a decrease in COX-2 expression. These findings indicate that melatonin restores Ca2+ homeostasis during AC and resolves inflammation. In addition, this indoleamine helps in the subsequent recovery of functionality.



J Physiol Pharmacol. 2007 Dec;58 Suppl 6:23-52.Click here to read Links

Role of melatonin in upper gastrointestinal tract.

Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, Cracow, Poland. mpkontur@cyf-kr.edu.pl

Melatonin, an indole formed enzymatically from L-tryptophan, is the most versatile and ubiquitous hormone molecule produced not only in all animals but also in some plants. This review focuses on the role of melatonin in upper portion of gastrointestinal tract (GIT), including oral cavity, esophagus, stomach and duodenum, where this indole is generated and released into the GIT lumen and into the portal circulation to be uptaken, metabolized by liver and released with bile into the duodenum. The biosynthetic steps of melatonin with two major rate limiting enzymes, arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT), transforming tryptophan to melatonin, originally identified in pinealocytes have been also detected in entero-endocrine (EE) cells of GIT wall, where this indole may act via endocrine, paracrine and/or luminal pathway through G-protein coupled receptors. Melatonin in GIT was shown to be generated in about 500 times larger amounts than it is produced in pineal gland. The production of melatonin by pineal gland shows circadian rhythm with high night-time peak, especially at younger age, followed by the fall during the day-light time. As a highly lipophilic substance, melatonin reaches all body cells within minutes, to serve as a convenient circadian timing signal for alteration of numerous body functions.. Following pinealectomy, the light/dark cycle of plasma melatonin levels disappears, while its day-time blood concentrations are attenuated but sustained mainly due to its release from the GIT. After oral application of tryptophan, the plasma melatonin increases in dose-dependent manner both in intact and pinealectomized animals, indicating that extrapineal sources such as GIT rather than pineal gland are the major producers of this indole. In the upper portion of GIT, melatonin exhibits a wide spectrum of activities such as circadian entrainment, free radicals scavenging activity, protection of mucosa against various irritants and healing of various GIT lesions such as stomatitis, esophagitis, gastritis and peptic ulcer. This review concentrates on the generation and pathophysiological implication of melatonin in upper GIT.


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