The overall purpose of this research proposal is to investigate the pathogenesis of the increased risk of cholesterol gallstones imposed by pregnancy and by taking female steroid hormones. Emphasis is placed upon studying effects of pregnancy and female steroid hormones on bile acid metabolism in human subjects. Bile acid kinetics will be measured using a newly developed method employing serum bile acids for estimating the rate of decay of administered cholic and chenodeoxycholic acids labelled with stable isotopes. Isotope abundance of 13C-labelled and 2H-labelled bile acids will be measured with gas chromatography/mass spectrometry/isotope ratiometry. Effects of pregnancy and female steroid hormones will be determined by serial and repeated studies during pregnancy and in the same subjects taking and not taking contraceptive steroids, estrogens, and progestins. Gallbladder storage and emptying, measured by realtime ultrasonography, and gastrointestinal transit, measured by the time of a breath hydrogen increase after oral lactulose, will be determined simultaneously. Cholecystectomized women will be compared with normal women. In some experiments sorbitol will be given to accelerate intestinal transit. These studies should indicate whether the increase in bile acid pool that occurs in such subjects is due to slowed enterohepatic circulation of bile acids or to hormonal stimulation of hepatic bile acid synthesis. The effects of pregnancy and female steroid hormones on hepatic incorporation of several precursors, labelled with stable isotopes, into bile acids will also be determined in intact subjects. The rate of synthesis of bile acids from precursor will be compared to the rate of synthesis determined by standard isotope dilution. These studies are designed to identify effects of pregnancy and female steroids on pathways of bile acid acid biosynthesis that might explain the disproportionate increase in cholic acid synthesis and pool size seen in pregnancy and during contraceptive steroid administration. The bile acid precursors, 7Alphahydroxy cholesterol, 7Alphahydroxy-4-cholesten-3-one, 26-hydroxycholesterol and 7Alpha, 26-hydroxy-4-cholesten-3-one will be studied.
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