CHOLELITHIASIS INDUCED IN THE SYRIAN-HAMSTER - EVIDENCE FOR AN INTRAMUCINOUS NUCLEATING PROCESS AND DOWN-REGULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE (CYP7) GENE BY MEDROXYPROGESTERONE

This report reviews previously published studies from our laboratory a nd shows some recent morphological data obtained with scanning and tra nsmission electron microscopy regarding gallstone formation and altera tion of the gallbladder epithelium in the Syrian hamster model. Both m ale and female hamsters were treated with female sex steroids (estradi ol alone, estradiol and medroxyprogesterone, medroxyprogesterone alone ) during one month. The results show that the Syrian hamster is a good model to study bile changes, gallbladder structure changes, including gallstone formation, and the regulation of cholesterol metabolism at the molecular level, Arguments in favor of this animal model are prese nted and, during gallstone formation, epithelial cell changes, anionic mucus secretion, and formation of gallbladder luminal deposits can be demonstrated. Recent molecular biology observations related to the ef fect of female sex steroids on liver cholesterol 7 alpha-hydroxylase ( CYP7) gene suggest that progestin alone or primed by estrogen down reg ulates CYP7 transcription and activity. In addition, progesterone in c ell culture systems has been shown to enhance intracellular accumulati on of free cholesterol by increasing its uptake and synthesis and by d ecreasing its esterification by inhibiting the activity of acylcoenzym e A: cholesterol acyltransferase. Non-esterified cholesterol is free t o migrate to the extracellular spaces and may contribute to nucleation within the bile. It is suggested that these effects of progesterone o n cholesterol metabolism combined with the CYP7 gene down regulation, physical changes in the mucus and the hypomotility of the gallbladder and biliary ducts result in hypersaturation of cholesterol in the bile which favors gallstone formation. (C) 1997 Wiley-Liss, Inc.